1
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Edwards S, Corrigan F, Collins-Praino L. Lasting Impact: Exploring the Brain Mechanisms that Link Traumatic Brain Injury to Parkinson's Disease. Mol Neurobiol 2025; 62:7421-7444. [PMID: 39891816 PMCID: PMC12078371 DOI: 10.1007/s12035-025-04706-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 01/14/2025] [Indexed: 02/03/2025]
Abstract
Development of Parkinson's Disease (PD) is linked with a history of traumatic brain injury (TBI), although the mechanisms driving this remain unclear. Of note, many key parallels have been identified between the pathologies of PD and TBI; in particular, PD is characterised by loss of dopaminergic neurons from the substantia nigra (SN), accompanied by broader changes to dopaminergic signalling, disruption of the Locus Coeruleus (LC) and noradrenergic system, and accumulation of aggregated α-synuclein in Lewy Bodies, which spreads in a stereotypical pattern throughout the brain. Widespread disruptions to the dopaminergic and noradrenergic systems, including progressive neuronal loss from the SN and LC, have been observed acutely following injury, some of which have also been identified chronically in TBI patients and preclinical models. Furthermore, changes to α-synuclein expression are also seen both acutely and chronically following injury throughout the brain, although detailed characterisation of these changes and spread of pathology is limited. In this review, we detail the current literature regarding dopaminergic and noradrenergic disruption and α-synuclein pathology following injury, with particular focus on how these changes may predispose individuals to prolonged pathology and progressive neurodegeneration, particularly the development of PD. While it is increasingly clear that TBI is a key risk factor for the development of PD, significant gaps remain in current understanding of neurodegenerative pathology following TBI, particularly chronic manifestations of injury.
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Affiliation(s)
- Samantha Edwards
- Cognition, Ageing and Neurodegenerative Disease Laboratory, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia
- Head Injury Lab, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Frances Corrigan
- Head Injury Lab, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia
| | - Lyndsey Collins-Praino
- Cognition, Ageing and Neurodegenerative Disease Laboratory, School of Biomedicine, The University of Adelaide, Adelaide, SA, 5005, Australia.
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2
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Mingo YB, Escobar Galvis ML, Henderson MX. α-Synuclein pathology and mitochondrial dysfunction: Toxic partners in Parkinson's disease. Neurobiol Dis 2025; 209:106889. [PMID: 40157617 DOI: 10.1016/j.nbd.2025.106889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 03/26/2025] [Accepted: 03/26/2025] [Indexed: 04/01/2025] Open
Abstract
Two major neuropathological features of Parkinson's disease (PD) are α-synuclein Lewy pathology and mitochondrial dysfunction. Although both α-synuclein pathology and mitochondrial dysfunction may independently contribute to PD pathogenesis, the interaction between these two factors is not yet fully understood. In this review, we discuss the physiological functions of α-synuclein and mitochondrial homeostasis in neurons as well as the pathological defects that ensue when these functions are disturbed in PD. Recent studies have highlighted that dysfunctional mitochondria can become sequestered within Lewy bodies, and cell biology studies have suggested that α-synuclein can directly impair mitochondrial function. There are also PD cases caused by genetic or environmental perturbation of mitochondrial homeostasis. Together, these studies suggest that mitochondrial dysfunction may be a common pathway to neurodegeneration in PD, triggered by multiple insults. We review the literature surrounding the interaction between α-synuclein and mitochondria and highlight open questions in the field that may be explored to advance our understanding of PD and develop novel, disease-modifying therapies.
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Affiliation(s)
- Yakum B Mingo
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, United States of America
| | | | - Michael X Henderson
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, United States of America.
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3
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Izco M, Sola C, Schleef M, Schmeer M, de Toro M, Verona G, Carlos E, Reinares-Sebastian A, Colina S, Marzo-Sola ME, Garcia-Sanmartin J, Fernández-Irigoyen J, Santamaría E, Mugica-Vidal R, Blesa J, Alvarez-Erviti L. Development of human targeted extracellular vesicles loaded with shRNA minicircles to prevent parkinsonian pathology. Transl Neurodegener 2025; 14:26. [PMID: 40420149 DOI: 10.1186/s40035-025-00484-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 04/09/2025] [Indexed: 05/28/2025] Open
Abstract
BACKGROUND Neurological disorders are the second leading cause of death and the leading cause of disability in the world. Thus, the development of novel disease-modifying strategies is clearly warranted. We have previously developed a therapeutic approach using mouse targeted rabies virus glycoprotein (RVG) extracellular vesicles (EVs) to deliver minicircles (MCs) expressing shRNA (shRNA-MCs) to induce long-term α-synuclein down-regulation. Although the previous therapy successfully reduced the pathology, the clinical translation was extremely unlikely since they were mouse extracellular vesicles. METHODS To overcome this limitation, we developed a source of human RVG-EVs compatible with a personalized therapy using immature dendritic cells. Human peripheral blood monocytes were differentiated in vitro into immature dendritic cells, which were transfected to express the RVG peptide. RVG-EVs containing shRNA-MCs, loaded by electroporation, were injected intravenously in the α-synuclein performed fibril (PFF) mouse model. Level of α-synuclein, phosphorylated α-synuclein aggregates, dopaminergic neurons and motor function were evaluated 90 days after the treatment. To confirm that EVs derived from patients were suitable as a vehicle, proteomic analysis of EVs derived from control, initial and advanced Parkinson's disease was performed. RESULTS The shRNA-MCs could be successfully loaded into human RVG-EVs and downregulate α-synuclein in SH-SY5Y cells. Intravenous injection of the shRNA-MC-loaded RVG-EVs induced long-term downregulation of α-synuclein mRNA expression and protein level, decreased α-synuclein aggregates, prevented dopaminergic cell death and ameliorated motor impairment in the α-synuclein PFF mouse model. Moreover, we confirmed that the EVs from PD patients are suitable as a personalized therapeutic vehicle. CONCLUSION Our study confirmed the therapeutic potential of shRNA-MCs delivered by human RVG-EVs for long-term treatment of neurodegenerative diseases. These results pave the way for clinical use of this approach.
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Affiliation(s)
- Maria Izco
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain.
| | - Carlos Sola
- Transfusion Center and Blood Bank of La Rioja, 26006, Logroño, Spain
| | | | | | - María de Toro
- Genomics and Bioinformatics Core Facility, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain
| | - Guglielmo Verona
- Centre for Amyloidosis, UCL Medical School, Rowland Hill Street, London, NW3 2PF, UK
| | - Estefania Carlos
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain
| | - Alejandro Reinares-Sebastian
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain
| | - Sandra Colina
- Servicio de Neurología, Hospital San Pedro, Piqueras 98, 26006, Logroño, Spain
| | | | - Josune Garcia-Sanmartin
- Angiogenesis Group, Oncology Area, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain
| | - Joaquín Fernández-Irigoyen
- Clinical Neuroproteomics Unit, Proteomics Platform, Navarrabiomed, Hospitalario, Universitario de Navarra (HUN), 31008, Pamplona, Spain
| | - Enrique Santamaría
- Clinical Neuroproteomics Unit, Proteomics Platform, Navarrabiomed, Hospitalario, Universitario de Navarra (HUN), 31008, Pamplona, Spain
| | - Rodolfo Mugica-Vidal
- Department of Mechanical Engineering, University of La Rioja, 26004, Logroño, Spain
| | - Javier Blesa
- HM CINAC (Centro Integral de Neurociencias Abarca Campal), Hospital Universitario HM Puerta del Sur, HM Hospitales, Madrid, Spain
- Instituto de Investigación Sanitaria HM Hospitales, Madrid, Spain
| | - Lydia Alvarez-Erviti
- Laboratory of Molecular Neurobiology, Center for Biomedical Research of La Rioja (CIBIR), 26006, Logroño, Spain.
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4
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Al-Lahham R, Corkins ME, Ishtikhar M, Rabadia P, Ramirez S, Banerjee V, Shahnawaz M. Intracellular Inclusions Induced by Patient-Derived and Amplified α-Synuclein Aggregates Are Morphologically Indistinguishable. Cells 2025; 14:684. [PMID: 40422187 PMCID: PMC12110328 DOI: 10.3390/cells14100684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2025] [Revised: 04/28/2025] [Accepted: 05/06/2025] [Indexed: 05/28/2025] Open
Abstract
Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients' brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients' brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients' CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients' brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients' brains, as well as those amplified from LBD and MSA patients' CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties.
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Affiliation(s)
- Rabab Al-Lahham
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Mark E. Corkins
- Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Mohd Ishtikhar
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Prakruti Rabadia
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Santiago Ramirez
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Victor Banerjee
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
| | - Mohammad Shahnawaz
- Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (M.I.); (P.R.); (S.R.)
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5
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Abstract
Both genetic and environmental factors modulate the risk of Parkinson's disease. In this article, all these pathophysiologic processes that contribute to damages at the tissue, cellular, organelle, and molecular levels, and their effects are talked about.
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Affiliation(s)
- Bin Xiao
- National Neuroscience Institute, Singapore; Duke-NUS Medical School, Singapore
| | - ZhiDong Zhou
- National Neuroscience Institute, Singapore; Duke-NUS Medical School, Singapore
| | - YinXia Chao
- National Neuroscience Institute, Singapore; Duke-NUS Medical School, Singapore
| | - Eng-King Tan
- National Neuroscience Institute, Singapore; Duke-NUS Medical School, Singapore.
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6
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Bellini G, D'Antongiovanni V, Palermo G, Antonioli L, Fornai M, Ceravolo R, Bernardini N, Derkinderen P, Pellegrini C. α-Synuclein in Parkinson's Disease: From Bench to Bedside. Med Res Rev 2025; 45:909-946. [PMID: 39704040 PMCID: PMC11976381 DOI: 10.1002/med.22091] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 09/24/2024] [Accepted: 11/07/2024] [Indexed: 12/21/2024]
Abstract
α-Synuclein (α-syn), a pathological hallmark of PD, is emerging as a bridging element at the crossroads between neuro/immune-inflammatory responses and neurodegeneration in PD. Several evidence show that pathological α-syn accumulates in neuronal and non-neuronal cells (i.e., neurons, microglia, macrophages, skin cells, and intestinal cells) in central and peripheral tissues since the prodromal phase of the disease, contributing to brain pathology. Indeed, pathological α-syn deposition can promote neurogenic/immune-inflammatory responses that contribute to systemic and central neuroinflammation associated with PD. After providing an overview of the structure and functions of physiological α-syn as well as its pathological forms, we review current studies about the role of neuronal and non-neuronal α-syn at the crossroads between neuroinflammation and neurodegeneration in PD. In addition, we provide an overview of the correlation between the accumulation of α-syn in central and peripheral tissues and PD, related symptoms, and neuroinflammation. Special attention was paid to discussing whether targeting α-syn can represent a suitable therapeutical approach for PD.
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Affiliation(s)
- Gabriele Bellini
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
- Department of NeurologyThe Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, NYU Langone HealthNew York CityNew YorkUSA
| | - Vanessa D'Antongiovanni
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Giovanni Palermo
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Luca Antonioli
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Matteo Fornai
- Unit of Pharmacology and Pharmacovigilance, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Roberto Ceravolo
- Center for Neurodegenerative Diseases, Unit of Neurology, Parkinson's Disease and Movement Disorders, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Nunzia Bernardini
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Pascal Derkinderen
- Department of NeurologyNantes Université, CHU Nantes, INSERMNantesFrance
| | - Carolina Pellegrini
- Unit of Histology and Embryology, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
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7
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Tabar V, Sarva H, Lozano AM, Fasano A, Kalia SK, Yu KKH, Brennan C, Ma Y, Peng S, Eidelberg D, Tomishima M, Irion S, Stemple W, Abid N, Lampron A, Studer L, Henchcliffe C. Phase I trial of hES cell-derived dopaminergic neurons for Parkinson's disease. Nature 2025; 641:978-983. [PMID: 40240592 PMCID: PMC12095069 DOI: 10.1038/s41586-025-08845-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 02/26/2025] [Indexed: 04/18/2025]
Abstract
Parkinson's disease is a progressive neurodegenerative condition with a considerable health and economic burden1. It is characterized by the loss of midbrain dopaminergic neurons and a diminished response to symptomatic medical or surgical therapy as the disease progresses2. Cell therapy aims to replenish lost dopaminergic neurons and their striatal projections by intrastriatal grafting. Here, we report the results of an open-label phase I clinical trial (NCT04802733) of an investigational cryopreserved, off-the-shelf dopaminergic neuron progenitor cell product (bemdaneprocel) derived from human embryonic stem (hES) cells and grafted bilaterally into the putamen of patients with Parkinson's disease. Twelve patients were enrolled sequentially in two cohorts-a low-dose (0.9 million cells, n = 5) and a high-dose (2.7 million cells, n = 7) cohort-and all of the participants received one year of immunosuppression. The trial achieved its primary objectives of safety and tolerability one year after transplantation, with no adverse events related to the cell product. At 18 months after grafting, putaminal 18Fluoro-DOPA positron emission tomography uptake increased, indicating graft survival. Secondary and exploratory clinical outcomes showed improvement or stability, including improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III OFF scores by an average of 23 points in the high-dose cohort. There were no graft-induced dyskinesias. These data demonstrate safety and support future definitive clinical studies.
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Affiliation(s)
- V Tabar
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY, USA.
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - H Sarva
- Department of Neurology, Weill Cornell Medicine, New York, NY, USA
| | - A M Lozano
- Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
- Krembil Brain Institute, Toronto, Ontario, Canada
| | - A Fasano
- Krembil Brain Institute, Toronto, Ontario, Canada
- Division of Neurology, University of Toronto, Toronto, Ontario, Canada
- Edmond J. Safra Program in Parkinson's Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Toronto, Ontario, Canada
| | - S K Kalia
- Division of Neurosurgery, University of Toronto, Toronto, Ontario, Canada
- Krembil Brain Institute, Toronto, Ontario, Canada
| | - K K H Yu
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - C Brennan
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Y Ma
- Center for Neurosciences, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - S Peng
- Center for Neurosciences, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - D Eidelberg
- Center for Neurosciences, Institute of Molecular Medicine, Feinstein Institutes for Medical Research, Manhasset, NY, USA
- Department of Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | | | - S Irion
- BlueRock Therapeutics, Cambridge, MA, USA
| | - W Stemple
- BlueRock Therapeutics, Cambridge, MA, USA
| | - N Abid
- BlueRock Therapeutics, Cambridge, MA, USA
| | - A Lampron
- BlueRock Therapeutics, Cambridge, MA, USA
| | - L Studer
- Center for Stem Cell Biology, Sloan Kettering Institute, New York, NY, USA
- Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - C Henchcliffe
- Department of Neurology, University of California, Irvine, CA, USA
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8
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Emborg ME, Metzger JM, D'Amour K, Colwell JC, Neumann LC, Zhang A, Federoff HJ. Advantages and challenges of using allogeneic vs. autologous sources for neuronal cell replacement in Parkinson's disease: Insights from non-human primate studies. Brain Res Bull 2025; 224:111297. [PMID: 40086764 PMCID: PMC12036832 DOI: 10.1016/j.brainresbull.2025.111297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 02/25/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]
Abstract
Intracerebral grafting of dopamine-producing cells is proposed as a strategy to replace the typical neurons lost to Parkinson's disease (PD) and improve PD motor symptoms. Non-human primate studies have provided clues on the relationship between the host's immune response and grafting success. Herein, we discuss how the host's immune system differentially affects the graft depending on the origin of the cells and reflect on the advantages and limitations of the immune paradigms utilized to assess graft-related outcomes. We also consider new strategies to minimize or circumvent the host's immunological response and related preclinical research needed to identify the most promising new approaches to be translated into the clinic.
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Affiliation(s)
- Marina E Emborg
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, USA; Department of Medical Physics, University of Wisconsin-Madison, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, USA.
| | - Jeanette M Metzger
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, USA
| | | | - Julia C Colwell
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, USA; Cellular and Molecular Pathology Graduate Program, University of Wisconsin-Madison, USA
| | - Lindsey C Neumann
- Preclinical Parkinson's Research Program, Wisconsin National Primate Research Center, University of Wisconsin-Madison, USA
| | - Ai Zhang
- Genentech, South San Francisco, CA, USA
| | - Howard J Federoff
- Kenai Therapeutics, San Diego, CA, USA; Georgetown University Medical Center, Washington, DC, USA
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9
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Li D, Liu K, Li D, Brunger A, Li C, Burré J, Diao J. α-Synuclein condensation in synaptic vesicle function and synucleinopathies. Trends Cell Biol 2025:S0962-8924(25)00087-X. [PMID: 40307115 DOI: 10.1016/j.tcb.2025.03.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 05/02/2025]
Abstract
Research into the crosstalk between α-synuclein (α-syn) and synaptic vesicles (SVs) has gained considerable attention. Notably, the recently discovered liquid-liquid phase separation of α-syn involving SVs is crucial for performing their physiological functions and mediating the transition to pathological aggregates. This review first examines the functional interactions between α-syn and SVs in the context of α-syn's condensation state. It then explores how these interactions become disrupted under pathological conditions, leading to α-syn aggregation and subsequent synaptic dysfunction. Finally, the review discusses the therapeutic potential of targeting α-syn-SV interactions to restore synaptic function in diseased states. By connecting α-syn's physiological roles with its pathological effects, the article aims to shed light on its dual role as both a regulator of SVs and a driver of neurodegeneration.
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Affiliation(s)
- Dan Li
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai 200030, China; Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, China.
| | - Kaien Liu
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China
| | - Danni Li
- School of Sensing Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Axel Brunger
- Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
| | - Cong Li
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201210, China; State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 200032, China; Shanghai Academy of Natural Sciences (SANS), Fudan University, Shanghai, China
| | - Jacqueline Burré
- Brain and Mind Research Institute & Appel Institute for Alzheimer's Disease Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Jiajie Diao
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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10
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Takahashi R, Yamakado H, Uemura N, Taguchi T, Ueda J. The Gut-Brain Axis Based on α-Synuclein Propagation-Clinical, Neuropathological, and Experimental Evidence. Int J Mol Sci 2025; 26:3994. [PMID: 40362234 PMCID: PMC12072079 DOI: 10.3390/ijms26093994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 04/17/2025] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
The cytopathological hallmark of Parkinson's disease (PD) is a neuronal cytoplasmic inclusion called Lewy body (LB). Lewy bodies are composed of alpha-synuclein (aSyn), a 140 aa protein that is predominantly expressed in the presynaptic terminal and which is implicated in neurotransmitter release. Recently, aSyn was found to propagate from neuron to neuron in a trans-synaptic manner. Although the precise molecular mechanisms are unclear, the propagation of aSyn is believed to play a major role in the progression of Lewy pathology in PD. Neuropathologically, the initial Lewy pathology has been shown to be formed in the dorsal motor nucleus of the vagus (DMV) or olfactory bulb by neuropathological studies. Since the DMV innervates the enteric nervous system (ENS) and LBs are formed in the gut nerve plexuses, it is conceivable that LBs propagate from the gut to the DMV and then to other regions of the brain. In this article, clinical, neuropathological, and experimental evidence supporting or negating the idea that aSyn propagation from the ENS to the brain leads to PD is reviewed. Moreover, the propagation of aSyn seeds through systemic circulation or multifocal generation of aSyn seeds is discussed as a potential alternative scenario for aSyn spreading.
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Affiliation(s)
- Ryosuke Takahashi
- Kyoto University Office of Research Acceleration, Kyoto 606-8501, Japan
| | - Hodaka Yamakado
- Department of Therapeutics for Multiple System Atrophy, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan;
| | - Norihito Uemura
- Department of Neurological Disease Control, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan;
| | - Tomoyuki Taguchi
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; (T.T.); (J.U.)
| | - Jun Ueda
- Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan; (T.T.); (J.U.)
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11
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Kim D, Huang Y, Liu J. Non-invasive MRI measurements of age-dependent in vivo human glymphatic exchange using magnetization transfer spin labeling. Neuroimage 2025; 310:121142. [PMID: 40089222 DOI: 10.1016/j.neuroimage.2025.121142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/25/2025] [Accepted: 03/12/2025] [Indexed: 03/17/2025] Open
Abstract
BACKGROUND The water exchange between brain parenchyma and cerebrospinal fluid (CSF) is considered to be responsible for glymphatic clearance of solutes and metabolic wastes from the brain, including amyloid-β, a biomarker in neurodegeneration. Despite the potential significance, no noninvasive technique for in vivo measurement of parenchyma-CSF water exchange has been demonstrated in humans, capable of investigating age-related changes in glymphatic clearance. PURPOSE To demonstrate a noninvasive, translatable MRI technique capable of measuring glymphatic water exchange in humans and to apply this technique to examine age-related changes in the glymphatic exchange measures in healthy subjects. METHODS Repeating on-resonance magnetization transfer (MT) RF pulses were applied to saturate macromolecules within the brain parenchyma and label its interstitial water, followed by measuring partial CSF saturation resulting from the parenchyma-CSF water exchange. Bloch simulations and phantom experiments determined the extent of direct CSF saturation by the MT pulses. An additional labeling nulling experiment was performed by preemptively saturating parenchyma spins to disable the following MT-based spin labeling, to examine non-exchange contributions to the observed CSF saturation. These techniques were applied to young (n = 6; ages 25-41) and elder (n = 6; ages 53-66) healthy participants to examine age-related changes in their saturation-based exchange measurements. RESULTS Both Bloch simulations and phantom experiments indicated small (0.4-0.7 %) direct CSF saturation when B0 inhomogeneities and CSF T2 variations were considered. A statistically significant (P = 0.037) difference was observed in the average CSF saturation ratio within the subarachnoid space (SAS) between the young (4.7 %±0.5 %) and the elder (3.5 %±1.2 %) subjects, with their ages negatively correlating with this exchange metric (R2=0.34, P = 0.046). The substantial saturation reductions in the labeling nulling experiment (40-50 % in young; 10-30 % in elder) suggested parenchyma-CSF exchange as a substantial source of the observed saturation signal. These findings survived when the exchange metrics were compensated for potential atrophy-related dilution effect caused by variations in intra-voxel CSF volume. CONCLUSION Optimized MT-based parenchyma spin labeling followed by CSF partial saturation measurement demonstrated feasibility of a noninvasive MRI approach to detect glymphatic water exchange between human brain parenchyma and CSF in vivo, with statistically significant findings of age-related differences in the exchange measures.
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Affiliation(s)
- Dahan Kim
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Yujia Huang
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Jiaen Liu
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX, United States; Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
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12
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Landolfi A, Sorrentino C, Barone P, Erro R. Biological frameworks for Parkinson's disease: the heterogeneity SAAgged. J Neurol 2025; 272:318. [PMID: 40186646 DOI: 10.1007/s00415-025-13049-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/13/2025] [Accepted: 03/18/2025] [Indexed: 04/07/2025]
Abstract
Recent biological frameworks of Parkinson's disease (PD) rely on the new advances in α-synuclein detection in biological tissues, mostly through α-synuclein seed amplification assays, and are mainly aimed at intercepting pre-clinical or early phases of disease to be subjected to disease-modifying therapies targeting α-synuclein. However, α-synuclein pathology alone is insufficient to explain the observed clinical heterogeneity of PD. Indeed, it has been demonstrated that a number of additional elements, such as genetics, comorbidities, co-pathology, and environmental factors, may influence PD phenotype and progression. Such factors have been partially accounted for or completely overlooked by both biological frameworks and would instead represent features which could explain, at least partially, the clinical and pathophysiologic diversities of PD and further represent potential druggable targets. Recognizing that the clinical heterogeneity of PD is a window to understand the pathophysiologic complexity of the disease might turn useful for a refinement of the current biological frameworks and move the field to satisfy the unmet need of establishing a precision medicine framework for this prevalent disorder.
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Affiliation(s)
- Annamaria Landolfi
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
| | - Cristiano Sorrentino
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
| | - Paolo Barone
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy
- IRCCS Synlab SDN, Naples, Italy
| | - Roberto Erro
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via S. Allende, 84081, Baronissi, SA, Italy.
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Ravanidis S, Bougea A, Koros C, Simitsi AM, Kokotis P, Stefanis L, Doxakis E. Plasma miRNA Biomarker Signatures in Parkinsonian Syndromes. Mol Neurobiol 2025:10.1007/s12035-025-04890-w. [PMID: 40184025 DOI: 10.1007/s12035-025-04890-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
Diagnosing atypical parkinsonian syndromes (APS) remains challenging due to overlapping clinical features and limited diagnostic tools. Brain-enriched microRNAs (miRNAs), which regulate neuronal development and function, are detectable in plasma and could serve as molecular biomarkers. This prospective study aimed to identify plasma brain-enriched miRNAs that can distinguish APS and elucidate affected molecular pathways. Reverse transcription-quantitative PCR (RT-qPCR) was performed on plasma samples from patients with idiopathic Parkinson's disease (iPD), multiple system atrophy (MSA), including the cerebellar subtype (MSA-C) and the parkinsonian subtype (MSA-P), progressive supranuclear palsy (PSP), and healthy controls. MiRNA expression analysis revealed distinct molecular fingerprints for each parkinsonian syndrome, with opposite trends between MSA and iPD compared to controls, suggesting distinct pathogenic mechanisms. Most dysregulated miRNAs clustered at chromosome (Chr)14q32 and shared binding sites for CREB1, CEBPB, and MAZ transcription factors. Pathway analysis revealed enrichment in prion diseases, Hippo signaling, TGF-beta signaling, and FoxO signaling pathways.
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Affiliation(s)
- Stylianos Ravanidis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
| | - Anastasia Bougea
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, 11528, Athens, Greece
| | - Christos Koros
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, 11528, Athens, Greece
| | - Athina-Maria Simitsi
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, 11528, Athens, Greece
| | - Panagiotis Kokotis
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, 11528, Athens, Greece
| | - Leonidas Stefanis
- Center of Clinical Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece
- First Department of Neurology, National and Kapodistrian University of Athens Medical School, 11528, Athens, Greece
| | - Epaminondas Doxakis
- Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527, Athens, Greece.
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14
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Raina A, Wang W, Gonzalez JC, Yan X, Overstreet-Wadiche L, Wadiche JI, Zhang CL, Chen SG. Distinct alpha-synuclein strains derived from Parkinson's disease patient tissues trigger differential inclusion pathology in a novel biosensor cell model. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.04.01.646513. [PMID: 40236210 PMCID: PMC11996501 DOI: 10.1101/2025.04.01.646513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Background α-Synuclein (αSyn) can misfold and aggregate to form fibrillar ß-sheet-rich aggregates ("strains") that are phosphorylated (p-αSyn) and deposited into intracellular inclusions in the brain, the pathological hallmark of synucleinopathies including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Previously, we reported that seed amplification assays such as real-time quaking-induced conversion (RT-QuIC) amplifies and detects αSyn strains from the patient skin. However, whether skin-derived αSyn strains induce disease-specific pathological features in a biological system is unknown. Methods We generated a U251 human glioblastoma cell line expressing fluorescently tagged αSyn carrying the PD-linked A53T mutation and Förster resonance energy transfer (FRET)-based U251 biosensor cells. Using fluorescence microscopy coupled with in situ detergent extraction, FRET-Flow cytometry and high-content confocal imaging, we examined the pathological burden and morphology of p-αSyn inclusions seeded by RT-QuIC-amplified patient skin and brain αSyn strains in αSyn-expressing U251 cells, FRET-based αSyn biosensor cells and αSyn biosensor cell-derived neurons. Results U251 cells allow robust and rapid in situ detection of detergent-insoluble intracellular αSyn inclusions triggered by exogenous αSyn seeds. In U251 FRET-based biosensor cells, PD skin-amplified strains induce a greater pathological burden and distinct p-αSyn inclusion morphology from PD brain-amplified and DLB skin-amplified strains. Inclusion morphology of DLB and MSA skin- and brain-amplified strains are comparable. Furthermore, skin-amplified αSyn strains induce neuronal inclusions and cause degeneration of induced neurons reprogrammed from the U251 biosensor cells. Finally, biosensor cell-propagated PD skin αSyn strains induce higher seeding activity measured by RT-QuIC than PD brain and DLB skin αSyn strains, linking intracellular pathological burden to in vitro seeding activity. Conclusions We report the detection of distinct PD strains derived from patient skin and brain tissues that trigger unique pathological phenotypes in U251 αSyn biosensor cells and cause degeneration of reprogrammed neurons from the same cell lineage. Moreover, DLB and MSA skin αSyn strains mimic pathological features of their brain αSyn strains in these biosensor cells. Therefore, the U251 αSyn biosensor cell model is a robust tool to potentially discriminate PD and DLB synucleinopathies and to study αSyn tissue- and strain-specific etiology and pathogenesis. Graphical abstract
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15
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Samidurai M, Chennakesavan K, Sarkar S, Malovic E, Nguyen HM, Singh L, Kumar A, Ealy A, Janarthanam C, Palanisamy BN, Kondru N, Zenitsky G, Jin H, Anantharam V, Kanthasamy A, Zhang H, Wulff H, Kanthasamy A. KCa3.1 Contributes to Neuroinflammation and Nigral Dopaminergic Neurodegeneration in Experimental models of Parkinson's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.18.643982. [PMID: 40166152 PMCID: PMC11956954 DOI: 10.1101/2025.03.18.643982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Chronic neuroinflammation and misfolded α-synuclein (αSyn) have been identified as key pathological correlates driving Parkinson's disease (PD) pathogenesis; however, the contribution of ion channels to microglia activation in the context of α-synucleinopathy remains elusive. Herein, we show that KCa3.1, a calcium-activated potassium channel, is robustly upregulated within microglia in multiple preclinical models of PD and, most importantly, in human PD and dementia with Lewy bodies (DLB) brains. Pharmacological inhibition of KCa3.1 via senicapoc or TRAM-34 inhibits KCa3.1 channel activity and the associated reactive microglial phenotype in response to aggregated αSyn, as well as ameliorates of PD like pathology in diverse PD mouse models. Additionally, proteomic and transcriptomic profiling of microglia revealed that senicapoc ameliorates aggregated αSyn-induced, inflammation-associated pathways and dysregulated metabolism in primary microglial cells. Mechanistically, FYN kinase in a STAT1 dependent manner regulates KCa3.1 mediated the microglial reactive activation phenotype after α-synucleinopathy. Moreover, reduced neuroinflammation and subsequent PD-like neuropathology were observed in SYN AAV inoculated KCa3.1 knockout mice. Together, these findings suggest that KCa3.1 inhibition represents a novel therapeutic strategy for treating patients with PD and related α-synucleinopathies.
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16
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Sirerol-Piquer MS, Perez-Villalba A, Duart-Abadia P, Belenguer G, Gómez-Pinedo U, Blasco-Chamarro L, Carrillo-Barberà P, Pérez-Cañamás A, Navarro-Garrido V, Dehay B, Vila M, Vitorica J, Pérez-Sánchez F, Fariñas I. Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species. Mol Neurodegener 2025; 20:26. [PMID: 40038767 PMCID: PMC11881471 DOI: 10.1186/s13024-025-00816-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Accepted: 02/19/2025] [Indexed: 03/06/2025] Open
Abstract
Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson's disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the recently uncovered microglial molecular diversity. Here, we show that periventricular microglia of the subependymal neurogenic niche monitor the cerebrospinal fluid and can rapidly phagocytize and degrade different aggregated forms of αSyn delivered into the lateral ventricle. However, this clearing ability worsens with age, leading to an increase in microglia with aggregates in aged treated mice, an accumulation also observed in human PD samples. We also show that exposure of aged microglia to aggregated αSyn isolated from human PD samples results in the phosphorylation of the endogenous protein and the generation of αSyn seeds that can transmit the pathology to healthy neurons. Our data indicate that while microglial phagocytosis rapidly clears toxic αSyn, aged microglia can contribute to synucleinopathy spreading.
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Affiliation(s)
- Mª Salomé Sirerol-Piquer
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain.
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain.
| | - Ana Perez-Villalba
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
- L.A.B.P. (Laboratory of Animal Behavior Phenotype), Facultad de Psicología. UCV, Valencia, Spain
| | - Pere Duart-Abadia
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Germán Belenguer
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Ulises Gómez-Pinedo
- Laboratory of Neurobiology, Institute of Neurosciences, Hospital Clínico San Carlos Health Research Institute, Universidad Complutense de Madrid, Madrid, Spain
| | - Laura Blasco-Chamarro
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Pau Carrillo-Barberà
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Azucena Pérez-Cañamás
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Victoria Navarro-Garrido
- Instituto de Biomedicina de Sevilla (IBiS), Universidad de Sevilla, Seville, Spain
- Departamento Bioquímica y Biología Molecular, Universidad de Sevilla, Seville, Spain
| | - Benjamin Dehay
- Univ. Bordeaux, CNRS, IMN, UMR 5293, Bordeaux, F-33000, France
| | - Miquel Vila
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Neurodegenerative Diseases Research Group, Vall d´Hebron Research Institute, Autonomous University of Barcelona, Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Javier Vitorica
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBiS), Universidad de Sevilla, Seville, Spain
- Departamento Bioquímica y Biología Molecular, Universidad de Sevilla, Seville, Spain
| | - Francisco Pérez-Sánchez
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain
| | - Isabel Fariñas
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain.
- Departamento de Biología Celular, Biología Funcional y Antropología Física, Universidad de Valencia, Burjassot, Spain.
- Instituto de Biotecnología y Biomedicina (BioTecMed), Universidad de Valencia, Burjassot, Spain.
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Lucas L, Tsoi PS, Quan MD, Choi KJ, Ferreon JC, Ferreon ACM. Tubulin transforms Tau and α-synuclein condensates from pathological to physiological. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.27.640500. [PMID: 40060635 PMCID: PMC11888465 DOI: 10.1101/2025.02.27.640500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/05/2025]
Abstract
Proteins phase-separate to form condensates that partition and concentrate biomolecules into membraneless compartments. These condensates can exhibit dichotomous behaviors in biology by supporting cellular physiology or instigating pathological protein aggregation 1-3 . Tau and α- synuclein (αSyn) are neuronal proteins that form heterotypic (Tau:αSyn) condensates associated with both physiological and pathological processes. Tau and αSyn functionally regulate microtubules 8-12 , but are also known to misfold and co-deposit in aggregates linked to various neurodegenerative diseases 4,5,6,7 , which highlights the paradoxically ambivalent effect of Tau:αSyn condensation in health and disease. Here, we show that tubulin modulates Tau:αSyn condensates by promoting microtubule interactions, competitively inhibiting the formation of homotypic and heterotypic pathological oligomers. In the absence of tubulin, Tau-driven protein condensation accelerates the formation of toxic Tau:αSyn heterodimers and amyloid fibrils. However, tubulin partitioning into Tau:αSyn condensates modulates protein interactions, promotes microtubule polymerization, and prevents Tau and αSyn oligomerization and aggregation. We distinguished distinct Tau and αSyn structural states adopted in tubulin-absent (pathological) and tubulin-rich (physiological) condensates, correlating compact conformations with aggregation and extended conformations with function. Furthermore, using various neuronal cell models, we showed that loss of stable microtubules, which occurs in Alzheimer's disease and Parkinsons disease patients 13,14 , results in pathological oligomer formation and loss of neurites, and that functional condensation using an inducible optogenetic Tau construct resulted in microtubule stablization. Our results identify that tubulin is a critical modulator in switching Tau:αSyn pathological condensates to physiological, mechanistically relating the loss of stable microtubules with disease progression. Tubulin restoration strategies and Tau-mediated microtubule stabilization can be potential therapies targeting both Tau-specific and Tau/αSyn mixed pathologies.
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Nuermaimaiti M, Ishikawa KI, Oyama G, Nonaka R, Shiga T, Jo T, Tsunemi T, Nakamura R, Krüger R, Akamatsu W, Hattori N. Human induced pluripotent stem cell-derived dopaminergic neurons release alpha-synuclein through neuronal activity. Neurosci Res 2025; 212:105-114. [PMID: 39617169 DOI: 10.1016/j.neures.2024.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 11/14/2024] [Accepted: 11/27/2024] [Indexed: 12/08/2024]
Abstract
Lewy body diseases, including Parkinson's disease (PD), are characterized by the spread of alpha-synuclein (αSyn) between neurons across synapses, a process crucial for understanding their pathophysiology and developing effective treatments. In this study, we aimed to investigate the role of neuronal activity in releasing αSyn from human induced pluripotent stem cell-derived dopaminergic neurons. We examined human induced pluripotent stem cell-derived dopaminergic neurons, both healthy and those with the αSyn gene mutation associated with PD. We employed pharmacological agents and optogenetic techniques and demonstrated that increased neuronal activity, induced by bicuculline or optogenetic stimulation, significantly enhances αSyn release. However, suppression of neuronal activity with cyanquixaline reduces αSyn secretion. These findings underscore the pivotal role of neuronal activity in αSyn transmission between neurons, showing its potential impact on the spread of Lewy pathology in patients with neurodegenerative diseases like PD. Therefore, this study advances our understanding of PD and opens new avenues for therapeutic strategies to mitigate Lewy body disease progression.
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Affiliation(s)
- Maierdanjiang Nuermaimaiti
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Department of Clinical Data of Parkinson's Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Kei-Ichi Ishikawa
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan.
| | - Genko Oyama
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Risa Nonaka
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Laboratory of Molecular Biology, Faculty of Pharmacy, Juntendo University, Chiba, Japan
| | - Takahiro Shiga
- Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Takayuki Jo
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Taiji Tsunemi
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Ryota Nakamura
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan
| | - Rejko Krüger
- Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Institute of Health, Strassen, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg
| | - Wado Akamatsu
- Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan
| | - Nobutaka Hattori
- Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan; Department of Clinical Data of Parkinson's Disease, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Center for Genomic and Regenerative Medicine, Graduate School of Medicine, Juntendo University, Tokyo, Japan; Department of Research and Development for Organoids, School of Medicine, Juntendo University, Tokyo, Japan; Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Luxembourg Institute of Health, Strassen, Luxembourg; Centre Hospitalier de Luxembourg, Luxembourg; Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Saitama, Japan
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Kim MS, Yoon S, Choi J, Kim YJ, Lee G. Stem Cell-Based Approaches in Parkinson's Disease Research. Int J Stem Cells 2025; 18:21-36. [PMID: 38449089 PMCID: PMC11867902 DOI: 10.15283/ijsc23169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 02/15/2024] [Accepted: 02/16/2024] [Indexed: 03/08/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of midbrain dopaminergic neurons, leading to motor symptoms. While current treatments provide limited relief, they don't alter disease progression. Stem cell technology, involving patient-specific stem cell-derived neurons, offers a promising avenue for research and personalized regenerative therapies. This article reviews the potential of stem cell-based research in PD, summarizing ongoing efforts, their limitations, and introducing innovative research models. The integration of stem cell technology and advanced models promises to enhance our understanding and treatment strategies for PD.
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Affiliation(s)
- Min Seong Kim
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Subeen Yoon
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
| | - Jiwoo Choi
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
| | - Yong Jun Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul, Korea
- Department of Pathology, College of Medicine, Kyung Hee University, Seoul, Korea
- KHU-KIST Department of Converging Science and Technology, Graduate School, Kyung Hee University, Seoul, Korea
| | - Gabsang Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Tullo S, Park J, Gallino D, Park M, Mar K, Novikov V, Sandoval Contreras R, Patel R, Del Cid-Pellitero E, Fon EA, Luo W, Shlaifer I, Durcan TM, Prado MAM, Prado VF, Devenyi GA, Chakravarty MM. Female mice exhibit resistance to disease progression despite early pathology in a transgenic mouse model inoculated with alpha-synuclein fibrils. Commun Biol 2025; 8:288. [PMID: 39987244 PMCID: PMC11846974 DOI: 10.1038/s42003-025-07680-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Accepted: 02/05/2025] [Indexed: 02/24/2025] Open
Abstract
Despite known sex differences in human synucleinopathies such as Parkinson's disease, the impact of sex on alpha-synuclein pathology in mouse models has been largely overlooked. To address this need, we examine sex differences in whole brain signatures of neurodegeneration due to aSyn toxicity in the M83 mouse model using longitudinal magnetic resonance imaging (MRI; T1-weighted; 100 μm3 isotropic voxel; -7, 30, 90 and 120 days post-injection [dpi]; n ≥ 8 mice/group/sex/time point). To initiate aSyn spreading, M83 mice are inoculated with recombinant human aSyn preformed fibrils (Hu-PFF) or phosphate buffered saline in the right striatum. We observe more aggressive neurodegenerative profiles over time for male Hu-PFF-injected mice when examining voxel-wise trajectories. However, at 90 dpi, we observe widespread patterns of neurodegeneration in the female Hu-PFF-injected mice. These differences are not accompanied by any differences in motor symptom onset between the sexes. However, male Hu-PFF-injected mice reached their humane endpoint sooner. These findings suggest that post-motor symptom onset, despite accelerated disease trajectories for male Hu-PFF-injected mice, neurodegeneration may appear sooner in the female Hu-PFF-injected mice (prior to motor symptomatology). These findings suggest that sex-specific synucleinopathy phenotypes urgently need to be considered to improve our understanding of neuroprotective and neurodegenerative mechanisms.
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Affiliation(s)
- Stephanie Tullo
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada.
| | - Janice Park
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
| | - Daniel Gallino
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
| | - Megan Park
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
| | - Kristie Mar
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
| | - Vladislav Novikov
- Robarts Research Institute, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
| | - Rodrigo Sandoval Contreras
- Robarts Research Institute, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
| | - Raihaan Patel
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
- Department of Biological & Biomedical Engineering, McGill University, Montreal, QC, Canada
| | - Esther Del Cid-Pellitero
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Edward A Fon
- Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Wen Luo
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Irina Shlaifer
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, QC, Canada
| | - Marco A M Prado
- Robarts Research Institute, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
| | - Vania F Prado
- Robarts Research Institute, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine, The University of Western Ontario, London, ON, Canada
| | - Gabriel A Devenyi
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada
- Department of Psychiatry, McGill University, Montreal, QC, Canada
| | - M Mallar Chakravarty
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada.
- Cerebral Imaging Center, Douglas Research Center, McGill University, Verdun, QC, Canada.
- Department of Biological & Biomedical Engineering, McGill University, Montreal, QC, Canada.
- Department of Psychiatry, McGill University, Montreal, QC, Canada.
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21
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Marmion DJ, Deng P, Hiller BM, Lewis RL, Harms LJ, Cameron DL, Nolta JA, Kordower JH, Fink KD, Wakeman DR. Long-Term Engraftment of Cryopreserved Human Neurons for In Vivo Disease Modeling in Neurodegenerative Disease. BIOLOGY 2025; 14:217. [PMID: 40001985 PMCID: PMC11852092 DOI: 10.3390/biology14020217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
The transplantation of human neurons into the central nervous system (CNS) offers transformative opportunities for modeling neurodegenerative diseases in vivo. This study evaluated the survival, integration, and functional properties of cryopreserved forebrain GABAergic neurons (iGABAs) derived from human induced pluripotent stem cells (iPSCs) across three species used in translational research. iGABAs were stereotactically injected into the striatum of Sprague-Dawley rats, immunodeficient RNU rats, R6/2 Huntington's disease (HD) mice, wild-type controls, and Cynomolgus monkeys. Post-transplantation, long-term assessments revealed robust neuronal survival, extensive neurite outgrowth, and integration with host CNS environments. In immunodeficient rats, iGABAs innervated the neuraxis, extending from the prefrontal cortex to the midbrain, while maintaining mature neuronal phenotypes without uncontrolled proliferation. Similarly, grafts in nonhuman primates showed localized survival and stable phenotype at one month. In the neurodegenerative milieu of HD mice, iGABAs survived up to six months, projecting into the host striatum and white matter, with evidence of mutant huntingtin aggregates localized within the graft, indicating pathological protein transfer. These findings underscore the utility of cryopreserved iGABAs as a reproducible, scalable model for disease-specific CNS investigations and mechanistic studies of proteinopathic propagation. This work establishes a critical platform for studying neurodegenerative diseases and developing therapeutic interventions.
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Affiliation(s)
- David J. Marmion
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Peter Deng
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Benjamin M. Hiller
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | | | - Lisa J. Harms
- FujiFilm Cellular Dynamics Inc., Madison, WI 53711, USA
| | - David L. Cameron
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Jan A. Nolta
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Jeffrey H. Kordower
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85281, USA
| | - Kyle D. Fink
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Dustin R. Wakeman
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Department of Psychiatry, Yale University, New Haven, CT 06511, USA
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22
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Sun YR, Lv QK, Liu JY, Wang F, Liu CF. New perspectives on the glymphatic system and the relationship between glymphatic system and neurodegenerative diseases. Neurobiol Dis 2025; 205:106791. [PMID: 39778750 DOI: 10.1016/j.nbd.2025.106791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/03/2025] [Accepted: 01/03/2025] [Indexed: 01/11/2025] Open
Abstract
Neurodegenerative diseases (ND) are characterized by the accumulation of aggregated proteins. The glymphatic system, through its rapid exchange mechanisms between cerebrospinal fluid (CSF) and interstitial fluid (ISF), facilitates the movement of metabolic substances within the brain, serving functions akin to those of the peripheral lymphatic system. This emerging waste clearance mechanism offers a novel perspective on the removal of pathological substances in ND. This article elucidates recent discoveries regarding the glymphatic system and updates relevant concepts within its model. It discusses the potential roles of the glymphatic system in ND, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple system atrophy (MSA), and proposes the glymphatic system as a novel therapeutic target for these conditions.
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Affiliation(s)
- Yan-Rui Sun
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Qian-Kun Lv
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China
| | - Jun-Yi Liu
- Department of Neurology, Dushu Lake hospital affilicated to Soochow University, Suzhou, China
| | - Fen Wang
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
| | - Chun-Feng Liu
- Department of Neurology and Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China; Jiangsu Key Laboratory of Neuropsychiatric Diseases and Institute of Neuroscience, Soochow University, Suzhou 215123, China.
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23
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Wiseman JA, Reddy K, Dieriks BV. From onset to advancement: the temporal spectrum of α-synuclein in synucleinopathies. Ageing Res Rev 2025; 104:102640. [PMID: 39667671 DOI: 10.1016/j.arr.2024.102640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 11/21/2024] [Accepted: 12/10/2024] [Indexed: 12/14/2024]
Abstract
This review provides an in-depth analysis of the complex role of alpha-synuclein (α-Syn) in the development of α-synucleinopathies, with a particular focus on its structural diversity and the resulting clinical variability. The ability of α-Syn to form different strains or polymorphs and undergo various post-translational modifications significantly contributes to the wide range of symptoms observed in disorders such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), as well as in lesser-known non-classical α-synucleinopathies. The interaction between genetic predispositions and environmental factors further complicates α-synucleinopathic disease pathogenesis, influencing the disease-specific onset and progression. Despite their common pathological hallmark of α-Syn accumulation, the clinical presentation and progression of α-synucleinopathies differ significantly, posing challenges for diagnosis and treatment. The intricacies of α-Syn pathology highlight the critical need for a deeper understanding of its biological functions and interactions within the neuronal environment to develop targeted therapeutic strategies. The precise point at which α-Syn aggregation transitions from being a byproduct of initial disease triggers to an active and independent driver of disease progression - through the propagation and acceleration of pathogenic processes - remains unclear. By examining the role of α-Syn across various contexts, we illuminate its dual role as both a marker and a mediator of disease, offering insights that could lead to innovative approaches for managing α-synucleinopathies.
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Affiliation(s)
- James A Wiseman
- Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand; Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia
| | - Kreesan Reddy
- Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand; Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia
| | - Birger Victor Dieriks
- Department of Anatomy and Medical Imaging, University of Auckland, Auckland, New Zealand; Centre for Brain Research, University of Auckland, Auckland 1023, New Zealand; Brain and Mind Centre & Faculty of Medicine and Health School of Medical Sciences, The University of Sydney, Sydney, NSW 2050, Australia.
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24
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Kuo G, Kumbhar R, Blair W, Dawson VL, Dawson TM, Mao X. Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions. Mol Neurodegener 2025; 20:10. [PMID: 39849529 PMCID: PMC11756073 DOI: 10.1186/s13024-025-00797-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Accepted: 01/05/2025] [Indexed: 01/25/2025] Open
Abstract
α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson's disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer's disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies.
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Affiliation(s)
- Grace Kuo
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Ramhari Kumbhar
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - William Blair
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA.
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Xiaobo Mao
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
- Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA, 70130-2685, USA.
- Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, USA.
- Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD, USA.
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25
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Sakunthala A, Maji SK. Deciphering the Seed Size-Dependent Cellular Internalization Mechanism for α-Synuclein Fibrils. Biochemistry 2025; 64:377-400. [PMID: 39762762 DOI: 10.1021/acs.biochem.4c00667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Aggregation of α-synuclein (α-Syn) and Lewy body (LB) formation are the key pathological events implicated in Parkinson's disease (PD) that spread in a prion-like manner. However, biophysical and structural characteristics of toxic α-Syn species and molecular events that drive early events in the propagation of α-Syn amyloids in a prion-like manner remain elusive. We used a neuronal cell model to demonstrate the size-dependent native biological activities of α-Syn fibril seeds. Biophysical characterization of the fibril seeds generated by controlled fragmentation indicated that increased fragmentation leads to a reduction in fibril size, correlating directly with the extent of fragmentation events. Although the size-based complexity of amyloid fibrils modulates their biological activities and fibril amplification pathways, it remains unclear how the variability of fibril seed size dictates its specific uptake mechanism into the cells. The present study elucidates the mechanism of α-Syn fibril internalization and how it is regulated by the size of fibril seeds. Further, we demonstrate that size-dependent endocytic pathways (dynamin-dependent clathrin/caveolin-mediated) are more prominent for the differential uptake of short fibril seeds compared to their longer counterparts. This size-dependent preference might contribute to the enhanced uptake and transcellular propagation of short α-Syn fibril seeds in a prion-like manner. Overall, the present study suggests that the physical dimension of α-Syn amyloid fibril seeds significantly influences their cellular uptake and pathological responses in the initiation and progression of PD.
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Affiliation(s)
- Arunima Sakunthala
- Sunita Sanghi Centre of Aging and Neurodegenerative Diseases (SCAN), Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
- Department of Biosciences& Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Samir K Maji
- Sunita Sanghi Centre of Aging and Neurodegenerative Diseases (SCAN), Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
- Department of Biosciences& Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
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26
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Chen L, Chehade HD, Chu HY. Motor cortical neuronal hyperexcitability associated with α-synuclein aggregation. NPJ Parkinsons Dis 2025; 11:18. [PMID: 39809792 PMCID: PMC11733020 DOI: 10.1038/s41531-024-00867-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Accepted: 12/27/2024] [Indexed: 01/16/2025] Open
Abstract
ΑBSTRACT: In Parkinson's disease (PD), Lewy pathology deposits in the cerebral cortex, but how the pathology disrupts cortical circuit integrity and function remains poorly understood. To begin to address this question, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. We reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Specifically, αSyn aggregates-bearing intratelencephalic neurons (ITNs) showed hyperexcitability, increased input resistance, and decreased cell capacitance, which were associated with impaired HCN channel function. Morphologically, the αSyn aggregates-bearing ITNs showed shrinkage of cell bodies and loss of dendritic spines. Last, we showed that partial dopamine depletion is not sufficient to alter thalamocortical transmission to cortical pyramidal neurons. Our results provide a novel mechanistic understanding of cortical circuit dysfunction in PD.
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Affiliation(s)
- Liqiang Chen
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, USA
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington, DC, 20007, USA
| | - Hiba Douja Chehade
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, USA
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington, DC, 20007, USA
| | - Hong-Yuan Chu
- Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, USA.
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, 49503, USA.
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington, DC, 20007, USA.
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27
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Gao V, Crawford CV, Burré J. The Gut-Brain Axis in Parkinson's Disease. Cold Spring Harb Perspect Med 2025; 15:a041618. [PMID: 38772708 PMCID: PMC11694753 DOI: 10.1101/cshperspect.a041618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/23/2024]
Abstract
Parkinson's disease (PD) involves both the central nervous system (CNS) and enteric nervous system (ENS), and their interaction is important for understanding both the clinical manifestations of the disease and the underlying disease pathophysiology. Although the neuroanatomical distribution of pathology strongly suggests that the ENS is involved in disease pathophysiology, there are significant gaps in knowledge about the underlying mechanisms. In this article, we review the clinical presentation and management of gastrointestinal dysfunction in PD. In addition, we discuss the current understanding of disease pathophysiology in the gut, including controversies about early involvement of the gut in disease pathogenesis. We also review current knowledge about gut α-synuclein and the microbiome, discuss experimental models of PD-linked gastrointestinal pathophysiology, and highlight areas for further research. Finally, we discuss opportunities to use the gut-brain axis for the development of biomarkers and disease-modifying treatments.
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Affiliation(s)
- Virginia Gao
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
- Parkinson's Disease and Movement Disorders Institute, Department of Neurology, Weill Cornell Medicine, New York, New York 10065, USA
- Division of Movement Disorders, The Neurological Institute of New York, Columbia University Irving Medical Center, New York, New York 10033, USA
| | - Carl V Crawford
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, New York 10065, USA
| | - Jacqueline Burré
- Appel Institute for Alzheimer's Disease Research and Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York 10021, USA
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28
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Park H, Kam TI, Dawson VL, Dawson TM. α-Synuclein pathology as a target in neurodegenerative diseases. Nat Rev Neurol 2025; 21:32-47. [PMID: 39609631 DOI: 10.1038/s41582-024-01043-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2024] [Indexed: 11/30/2024]
Abstract
α-Synuclein misfolds into pathological forms that lead to various neurodegenerative diseases known collectively as α-synucleinopathies. In this Review, we provide a comprehensive overview of pivotal advances in α-synuclein research. We examine structural features and physiological functions of α-synuclein and summarize current insights into key post-translational modifications, such as nitration, phosphorylation, ubiquitination, sumoylation and truncation, considering their contributions to neurodegeneration. We also highlight the existence of disease-specific α-synuclein strains and their mechanisms of pathological spread, and discuss seed amplification assays and PET tracers as emerging diagnostic tools for detecting pathological α-synuclein in clinical settings. We also discuss α-synuclein aggregation and clearance mechanisms, and review cell-autonomous and non-cell-autonomous processes that contribute to neuronal death, including the roles of adaptive and innate immunity in α-synuclein-driven neurodegeneration. Finally, we highlight promising therapeutic approaches that target pathological α-synuclein and provide insights into emerging areas of research.
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Affiliation(s)
- Hyejin Park
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Tae-In Kam
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
- Department of Brain and Cognitive Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea
| | - Valina L Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ted M Dawson
- Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Adrienne Helis Malvin and Diana Helis Henry Medical Research Foundation, New Orleans, LA, USA.
- Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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29
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Alfaidi M, Barker RA, Kuan WL. An update on immune-based alpha-synuclein trials in Parkinson's disease. J Neurol 2024; 272:21. [PMID: 39666171 PMCID: PMC11638298 DOI: 10.1007/s00415-024-12770-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/24/2024] [Accepted: 10/25/2024] [Indexed: 12/13/2024]
Abstract
Parkinson's disease (PD) is a prevalent, chronic neurodegenerative disorder characterised by the progressive loss of dopaminergic neurons in the substantia nigra and other brain regions. The aggregation of alpha-synuclein (α-syn) into Lewy bodies and neurites is a key pathological feature associated with PD and its progression. Many therapeutic studies aim to target these aggregated forms of α-syn to potentially slow down or stop disease progression in PD. This review provides a comprehensive analysis of recent clinical trials involving vaccines and monoclonal antibodies targeting α-syn. Specifically, UB-312, AFFITOPE PD01A, PD03A and ACI-7104.056 are designed to provoke an immune response against α-syn (active immunisation), while Prasinezumab and Cinpanemab, MEDI1341 and Lu AF82422 focus on directly targeting α-syn aggregates (passive immunisation). Despite some promising results, challenges such as variable efficacy and trial discontinuations persist. Future research must address these challenges to advance disease-modifying therapies for PD around this therapeutic target.
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Affiliation(s)
- Maha Alfaidi
- John Van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Cambridge, CB2 0PY, UK.
| | - Roger A Barker
- John Van Geest Centre for Brain Repair and Department of Clinical Neuroscience, University of Cambridge, Cambridge, CB2 0PY, UK
- Department of Neurology, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
- Wellcome Trust- MRC Cambridge Stem Cell Centre, Cambridge, CB2 1QR, UK
- ALBORADA Drug Discovery Institute, Cambridge, CB2 0AH, UK
| | - Wei-Li Kuan
- ALBORADA Drug Discovery Institute, Cambridge, CB2 0AH, UK
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30
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Ioghen OC, Gaina G, Lambrescu I, Manole E, Pop S, Niculescu TM, Mosoia O, Ceafalan LC, Popescu BO. Bacterial products initiation of alpha-synuclein pathology: an in vitro study. Sci Rep 2024; 14:30306. [PMID: 39639092 PMCID: PMC11621565 DOI: 10.1038/s41598-024-81020-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 11/22/2024] [Indexed: 12/07/2024] Open
Abstract
Parkinson's Disease (PD) is a prevalent and escalating neurodegenerative disorder with significant societal implications. Despite being considered a proteinopathy, in which the aggregation of α-synuclein is the main pathological change, the intricacies of PD initiation remain elusive. Recent evidence suggests a potential link between gut microbiota and PD initiation, emphasizing the need to explore the effects of microbiota-derived molecules on neuronal cells. In this study, we exposed dopaminergic-differentiated SH-SY5Y cells to microbial molecules such as lipopolysaccharide (LPS), rhamnolipid, curli CsgA and phenol soluble modulin α-1 (PSMα1). We assessed cellular viability, cytotoxicity, growth curves and α-synuclein levels by performing MTS, LDH, real-time impedance readings, qRT-PCR and Western Blot assays respectively. Statistical analysis revealed that rhamnolipid exhibited concentration-dependent effects, reducing viability and inducing cytotoxicity at higher concentrations, increasing α-synuclein mRNA and protein levels with negative effects on cell morphology and adhesion. Furthermore, LPS exposure also increased α-synuclein levels. Curli CsgA and PSMα-1 showed minimal or no changes. Our findings suggest that microbiota-derived molecules, particularly rhamnolipid and LPS, impact dopaminergic neurons by increasing α-synuclein levels. This study highlights the potential involvement of gut microbiota in initiating the upregulation of α-synuclein that may further initiate PD, indicating the complex interplay between microbiota and neuronal cells.
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Grants
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
- 31PFE/30.12.2021 Ministry of Research, Innovation, and Digitalization in Romania
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Affiliation(s)
- Octavian Costin Ioghen
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
- "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania
| | - Gisela Gaina
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
- "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania
| | - Ioana Lambrescu
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
- "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania
| | - Emilia Manole
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
| | - Sevinci Pop
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
| | | | - Oana Mosoia
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
| | - Laura Cristina Ceafalan
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania.
- "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania.
| | - Bogdan Ovidiu Popescu
- "Victor Babeș" National Institute of Pathology, 050096, Bucharest, Romania
- "Carol Davila" University of Medicine and Pharmacy, 050474, Bucharest, Romania
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31
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Hattori N, Sato S. Mitochondrial dysfunction in Parkinson's disease. J Neural Transm (Vienna) 2024; 131:1415-1428. [PMID: 39585446 DOI: 10.1007/s00702-024-02863-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/05/2024] [Indexed: 11/26/2024]
Abstract
The exact cause of nigral cell death in Parkinson's disease (PD) is still unknown. However, research on MPTP-induced experimental parkinsonism has significantly advanced our understanding. In this model, it is widely accepted that mitochondrial respiratory failure is the primary mechanism of cell death. Studies have shown that a toxic metabolite of MPTP inhibits Complex I and alpha-ketoglutarate dehydrogenase activities in mitochondria. Since then, many research groups have focused on mitochondrial dysfunction in PD, identifying deficiencies in Complex I or III in PD patients' brains, skeletal muscle, and platelets. There is some debate about the decline in mitochondrial function in peripheral organs. However, since α-synuclein, the main component protein of Lewy bodies, accumulates in peripheral organs, it is reasonable to consider PD a systemic disease. Additionally, mutant mitochondrial DNA with a 4,977 base pair deletion has been found in the brains of PD patients, suggesting that age-related accumulation of deleted mtDNA is accelerated in the striatum and may contribute to the pathophysiology of PD. While the cause of PD remains unknown, mitochondrial dysfunction is undoubtedly a factor in cell death in PD. In addition, the causative gene for familial PD, parkin (now PRKN), and PTEN-induced putative kinase 1 (PINK1), both gene products are also involved in mitochondrial quality control. Moreover, we have successfully isolated and identified CHCHD2, which is involved in the mitochondrial electron transfer system. There is no doubt that mitochondrial dysfunction contributes to cell death in PD.
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Affiliation(s)
- Nobutaka Hattori
- Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo, Tokyo, 113-8421, Japan.
- Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, 2-1-Hirosawa, Wako-Shi, Saitama, 351-0198, Japan.
| | - Shigeto Sato
- Department of Neurology, Faculty of Medicine, Juntendo University, 2-1-1 Hongo, Bunkyo, Tokyo, 113-8421, Japan
- Center for Biomedical Research Resources, Juntendo University Graduate School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo, 113-8421, Japan
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32
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Barker RA, Björklund A, Parmar M. The history and status of dopamine cell therapies for Parkinson's disease. Bioessays 2024; 46:e2400118. [PMID: 39058892 PMCID: PMC11589688 DOI: 10.1002/bies.202400118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 06/26/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024]
Abstract
Parkinson's disease (PD) is characterized by the loss of the dopaminergic nigrostriatal pathway which has led to the successful development of drug therapies that replace or stimulate this network pharmacologically. Although these drugs work well in the early stages of the disease, over time they produce side effects along with less consistent clinical benefits to the person with Parkinson's (PwP). As such there has been much interest in repairing this pathway using transplants of dopamine neurons. This work which began 50 years ago this September is still ongoing and has now moved to first in human trials using human pluripotent stem cell-derived dopaminergic neurons. The results of these trials are eagerly awaited although proof of principle data has already come from trials using human fetal midbrain dopamine cell transplants. This data has shown that developing dopamine cells when transplanted in the brain of a PwP can survive long term with clinical benefits lasting decades and with restoration of normal dopaminergic innervation in the grafted striatum. In this article, we discuss the history of this field and how this has now led us to the recent stem cell trials for PwP.
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Affiliation(s)
- Roger A. Barker
- Department of Clinical Neurosciences and Cambridge Stem Cell InstituteJohn van Geest Centre for Brain RepairUniversity of CambridgeCambridgeUK
| | - Anders Björklund
- Department of Experimental Medical ScienceWallenberg Neuroscience CenterLund UniversityLundSweden
| | - Malin Parmar
- Department of Experimental Medical ScienceWallenberg Neuroscience CenterLund UniversityLundSweden
- Department of Clinical Sciences LundLund Stem Cell Center and Division of NeurologyLund UniversityLundSweden
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33
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Rokad D, Harischandra DS, Samidurai M, Chang YT, Luo J, Lawana V, Sarkar S, Palanisamy BN, Manne S, Kim D, Zenitsky G, Jin H, Anantharam V, Willette A, Kanthasamy A, Kanthasamy AG. Manganese Exposure Enhances the Release of Misfolded α-Synuclein via Exosomes by Impairing Endosomal Trafficking and Protein Degradation Mechanisms. Int J Mol Sci 2024; 25:12207. [PMID: 39596274 PMCID: PMC11594990 DOI: 10.3390/ijms252212207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 11/07/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Excessive exposure to manganese (Mn) increases the risk of chronic neurological diseases, including Parkinson's disease (PD) and other related Parkinsonisms. Aggregated α-synuclein (αSyn), a hallmark of PD, can spread to neighboring cells by exosomal release from neurons. We previously discovered that Mn enhances its spread, triggering neuroinflammatory and neurodegenerative processes. To better understand the Mn-induced release of exosomal αSyn, we examined the effect of Mn on endosomal trafficking and misfolded protein degradation. Exposing MN9D dopaminergic neuronal cells stably expressing human wild-type (WT) αSyn to 300 μM Mn for 24 h significantly suppressed protein and mRNA expression of Rab11a, thereby downregulating endosomal recycling, forcing late endosomes to mature into multivesicular bodies (MVBs). Ectopic expression of WT Rab11a significantly mitigated exosome release, whereas ectopic mutant Rab11a (S25N) increased it. Our in vitro and in vivo studies reveal that Mn exposure upregulated (1) mRNA and protein levels of endosomal Rab27a, which mediates the fusion of MVBs with the plasma membrane; and (2) expression of the autophagosomal markers Beclin-1 and p62, but downregulated the lysosomal marker LAMP2, thereby impairing autophagolysosome formation as confirmed by LysoTracker, cathepsin, and acridine orange assays. Our novel findings demonstrate that Mn promotes the exosomal release of misfolded αSyn by impairing endosomal trafficking and protein degradation.
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Affiliation(s)
- Dharmin Rokad
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Dilshan S. Harischandra
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Manikandan Samidurai
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Yuan-Teng Chang
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Jie Luo
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Vivek Lawana
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Souvarish Sarkar
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Bharathi N. Palanisamy
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Sireesha Manne
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Dongsuk Kim
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
| | - Gary Zenitsky
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Huajun Jin
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Vellareddy Anantharam
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Auriel Willette
- Department of Neurology, Rutgers University, New Brunswick, NJ 07101, USA;
| | - Arthi Kanthasamy
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
| | - Anumantha G. Kanthasamy
- Parkinson’s Disorder Research Program, Iowa Center for Advanced Neurotoxicology, Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA; (D.R.); (D.S.H.); (J.L.); (V.L.); (S.S.); (B.N.P.); (S.M.); (D.K.)
- Isakson Center for Neurological Disease Research, Department of Physiology and Pharmacology, University of Georgia, 325 Riverbend Road, Athens, GA 30602, USA; (M.S.); (Y.-T.C.); (G.Z.); (H.J.); (V.A.); (A.K.)
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34
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Ho HH, Wing SS. α-Synuclein ubiquitination - functions in proteostasis and development of Lewy bodies. Front Mol Neurosci 2024; 17:1498459. [PMID: 39600913 PMCID: PMC11588729 DOI: 10.3389/fnmol.2024.1498459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 10/22/2024] [Indexed: 11/29/2024] Open
Abstract
Synucleinopathies are neurodegenerative disorders characterized by the accumulation of α-synuclein containing Lewy bodies. Ubiquitination, a key post-translational modification, has been recognized as a pivotal regulator of α-synuclein's cellular dynamics, influencing its degradation, aggregation, and associated neurotoxicity. This review examines comprehensively the current understanding of α-synuclein ubiquitination and its role in the pathogenesis of synucleinopathies, particularly in the context of Parkinson's disease. We explore the molecular mechanisms responsible for α-synuclein ubiquitination, with a focus on the roles of E3 ligases and deubiquitinases implicated in the degradation process which occurs primarily through the endosomal lysosomal pathway. The review further discusses how the dysregulation of these mechanisms contributes to α-synuclein aggregation and LB formation and offers suggestions for future investigations into the role of α-synuclein ubiquitination. Understanding these processes may shed light on potential therapeutic avenues that can modulate α-synuclein ubiquitination to alleviate its pathological impact in synucleinopathies.
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Affiliation(s)
- Hung-Hsiang Ho
- Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Simon S. Wing
- Department of Medicine, McGill University and Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
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35
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Andrade GCD, Mota MF, Moreira-Ferreira DN, Silva JL, de Oliveira GAP, Marques MA. Protein aggregation in health and disease: A looking glass of two faces. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 145:145-217. [PMID: 40324846 DOI: 10.1016/bs.apcsb.2024.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Protein molecules organize into an intricate alphabet of twenty amino acids and five architecture levels. The jargon "one structure, one functionality" has been challenged, considering the amount of intrinsically disordered proteins in the human genome and the requirements of hierarchical hetero- and homo-protein complexes in cell signaling. The assembly of large protein structures in health and disease is now viewed through the lens of phase separation and transition phenomena. What drives protein misfolding and aggregation? Or, more fundamentally, what hinders proteins from maintaining their native conformations, pushing them toward aggregation? Here, we explore the principles of protein folding, phase separation, and aggregation, which hinge on crucial events such as the reorganization of solvents, the chemical properties of amino acids, and their interactions with the environment. We focus on the dynamic shifts between functional and dysfunctional states of proteins and the conditions that promote protein misfolding, often leading to disease. By exploring these processes, we highlight potential therapeutic avenues to manage protein aggregation and reduce its harmful impacts on health.
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Affiliation(s)
- Guilherme C de Andrade
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil
| | - Michelle F Mota
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil
| | - Dinarte N Moreira-Ferreira
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil
| | - Jerson L Silva
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil
| | - Guilherme A P de Oliveira
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil.
| | - Mayra A Marques
- Institute of Medical Biochemistry Leopoldo de Meis, National Institute of Science and Technology for Structural Biology, Federal University of Rio de Janeiro, Rio De Janeiro, RJ, Brazil.
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36
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Liu J, Ji Z, He Q, Chen H, Xu X, Mei Q, Hu Y, Zhang H. Direct conversion of human umbilical cord mesenchymal stem cells into dopaminergic neurons for Parkinson's disease treatment. Neurobiol Dis 2024; 201:106683. [PMID: 39343249 DOI: 10.1016/j.nbd.2024.106683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/22/2024] [Accepted: 09/25/2024] [Indexed: 10/01/2024] Open
Abstract
Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor deficits due to the depletion of nigrostriatal dopamine. Stem cell differentiation therapy emerges as a promising treatment option for sustained symptom relief. In this study, we successfully developed a one-step differentiation system using the YFBP cocktail (Y27632, Forskolin, SB431542, and SP600125) to effectively convert human umbilical cord mesenchymal stem cells (hUCMSCs) into dopaminergic neurons without genetic modification. This approach addresses the challenge of rapidly and safely generating functional neurons on a large scale. After a 7-day induction period, over 80 % of the cells were double-positive for TUBB3 and NEUN. Transcriptome analysis revealed the dual roles of the cocktail in inducing fate erasure in mesenchymal stem cells and activating the neuronal program. Notably, these chemically induced cells (CiNs) did not express HLA class II genes, preserving their immune-privileged status. Further study indicated that YFBP significantly downregulated p53 signaling and accelerated the differentiation process when Pifithrin-α, a p53 signaling inhibitor, was applied. Additionally, Wnt/β-catenin signaling was transiently activated within one day, but the prolonged activation hindered the neuronal differentiation of hUCMSCs. Upon transplantation into the striatum of mice, CiNs survived well and tested positive for dopaminergic neuron markers. They exhibited typical action potentials and sodium and potassium ion channel activity, demonstrating neuronal electrophysiological activity. Furthermore, CiNs treatment significantly increased the number of tyrosine hydroxylase-positive cells and the concentration of dopamine in the striatum, effectively ameliorating movement disorders in PD mice. Overall, our study provides a secure and reliable framework for cell replacement therapy for Parkinson's disease.
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Affiliation(s)
- Jinming Liu
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Zhongqing Ji
- Department of Orthopedics, Suzhou Yongding Hospital, Suzhou 215200, China
| | - Qisheng He
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Huanhuan Chen
- The Suqian Clinical College of Xuzhou Medical University, Suqian 223800, China
| | - Xiaojing Xu
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Qiuhao Mei
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Ya'nan Hu
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China.
| | - Huanxiang Zhang
- Department of Cell Biology, MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China.
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37
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Kelser BM, Teichner EM, Subtirelu RC, Hoss KN. A review of proposed mechanisms for neurodegenerative disease. Front Aging Neurosci 2024; 16:1370580. [PMID: 39439710 PMCID: PMC11493710 DOI: 10.3389/fnagi.2024.1370580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases.
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Affiliation(s)
- Benjamin M. Kelser
- School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Eric M. Teichner
- Sidney Kimmel Medical College (SKMC), Philadelphia, PA, United States
| | - Robert C. Subtirelu
- Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Kevin N. Hoss
- School of Medicine, Case Western Reserve University, Cleveland, OH, United States
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38
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Kalia LV, Berg D, Kordower JH, Shannon KM, Taylor JP, Cardoso F, Goldman JG, Jeon B, Meissner WG, Tijssen MAJ, Burn DJ, Fung VSC. International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions. Mov Disord 2024; 39:1710-1715. [PMID: 39250594 DOI: 10.1002/mds.30007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 09/11/2024] Open
Affiliation(s)
- Lorraine V Kalia
- Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada
- Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Daniela Berg
- Department of Neurology, University Hospital Schleswig-Holstein, Campus Kiel and Christian Albrechts-University of Kiel, Kiel, Germany
| | - Jeffery H Kordower
- ASU-Banner Neurodegenerative Disease Research Center, Tempe, Arizona, USA
- School of Life Sciences, Arizona State University, Tempe, Arizona, USA
| | - Kathleen M Shannon
- Department of Neurology, University of Wisconsin School of Public Health, Madison, Wisconsin, USA
| | - John-Paul Taylor
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Francisco Cardoso
- Movement Disorders Unit, Neurology Service, Internal Medicine Department, The Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Jennifer G Goldman
- Barrow Neurological Institute, Phoenix, Arizona, USA
- JPG Enterprises LLC, Chicago, Illinois, USA
| | - Beomseok Jeon
- BJ Center for Comprehensive Parkinson Care and Rare Movement Disorders, Chung-Ang University Health Care System, Hyundae Hospital, Namyangju-si, South Korea
| | - Wassilos G Meissner
- CHU Bordeaux, Service de Neurologie des Maladies Neurodégénératives, IMNc, Bordeaux, France
- Univ. Bordeaux, CNRS, IMN, UMR5293, Bordeaux, France
- Department of Medicine, University of Otago, Christchurch, and New Zealand Brain Research Institute, Christchurch, New Zealand
| | - Marina A J Tijssen
- Department of Neurology, Expertise Centre Movement Disorders, University Medical Centre Groningen, Groningen, The Netherlands
| | - David J Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Victor S C Fung
- Movement Disorders Unit, Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
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39
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Lázaro DF, Lee VMY. Navigating through the complexities of synucleinopathies: Insights into pathogenesis, heterogeneity, and future perspectives. Neuron 2024; 112:3029-3042. [PMID: 38861985 PMCID: PMC11427175 DOI: 10.1016/j.neuron.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/22/2024] [Accepted: 05/14/2024] [Indexed: 06/13/2024]
Abstract
The aggregation of alpha-synuclein (aSyn) represents a neuropathological hallmark observed in a group of neurodegenerative disorders collectively known as synucleinopathies. Despite their shared characteristics, these disorders manifest diverse clinical and pathological phenotypes. The mechanism underlying this heterogeneity is thought to be due to the diversity in the aSyn strains present across the diseases. In this perspective, we will explore recent findings on aSyn strains and discuss recent discoveries about Lewy bodies' composition. We further discuss the current hypothesis for aSyn spreading and emphasize the emerging biomarker field demonstrating promising results. A comprehension of these mechanisms holds substantial promise for future clinical applications. This understanding can pave the way for the development of personalized medicine strategies, specifically targeting the unique underlying causes of each synucleinopathy. Such advancements can revolutionize therapeutic approaches and significantly contribute to more effective interventions in the intricate landscape of neurodegenerative disorders.
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Affiliation(s)
- Diana F Lázaro
- Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Medicine, University of Pennsylvania, Perelman School of Medicine at University of Pennsylvania, 3600 Spruce Street, 3 Maloney Building, Philadelphia, PA 19104, USA.
| | - Virginia M-Y Lee
- Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Medicine, University of Pennsylvania, Perelman School of Medicine at University of Pennsylvania, 3600 Spruce Street, 3 Maloney Building, Philadelphia, PA 19104, USA.
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40
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Paulėkas E, Vanagas T, Lagunavičius S, Pajėdienė E, Petrikonis K, Rastenytė D. Navigating the Neurobiology of Parkinson's: The Impact and Potential of α-Synuclein. Biomedicines 2024; 12:2121. [PMID: 39335634 PMCID: PMC11429448 DOI: 10.3390/biomedicines12092121] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 09/15/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide; therefore, since its initial description, significant progress has been made, yet a mystery remains regarding its pathogenesis and elusive root cause. The widespread distribution of pathological α-synuclein (αSyn) aggregates throughout the body raises inquiries regarding the etiology, which has prompted several hypotheses, with the most prominent one being αSyn-associated proteinopathy. The identification of αSyn protein within Lewy bodies, coupled with genetic evidence linking αSyn locus duplication, triplication, as well as point mutations to familial Parkinson's disease, has underscored the significance of αSyn in initiating and propagating Lewy body pathology throughout the brain. In monogenic and sporadic PD, the presence of early inflammation and synaptic dysfunction leads to αSyn aggregation and neuronal death through mitochondrial, lysosomal, and endosomal functional impairment. However, much remains to be understood about αSyn pathogenesis, which is heavily grounded in biomarkers and treatment strategies. In this review, we provide emerging new evidence on the current knowledge about αSyn's pathophysiological impact on PD, and its presumable role as a specific disease biomarker or main target of disease-modifying therapies, highlighting that this understanding today offers the best potential of disease-modifying therapy in the near future.
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Affiliation(s)
- Erlandas Paulėkas
- Department of Neurology, Lithuanian University of Health Sciences Kaunas Clinics, LT-50161 Kaunas, Lithuania; (T.V.); (S.L.); (E.P.); (K.P.); (D.R.)
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41
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Wu S, Schekman RW. Intercellular transmission of alpha-synuclein. Front Mol Neurosci 2024; 17:1470171. [PMID: 39324117 PMCID: PMC11422390 DOI: 10.3389/fnmol.2024.1470171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 08/28/2024] [Indexed: 09/27/2024] Open
Abstract
An emerging theme in Parkinson's disease (PD) is the propagation of α-synuclein pathology as the disease progresses. Research involving the injection of preformed α-synuclein fibrils (PFFs) in animal models has recapitulated the pathological spread observed in PD patients. At the cellular and molecular levels, this intercellular spread requires the translocation of α-synuclein across various membrane barriers. Recent studies have identified subcellular organelles and protein machineries that facilitate these processes. In this review, we discuss the proposed pathways for α-synuclein intercellular transmission, including unconventional secretion, receptor-mediated uptake, endosome escape and nanotube-mediated transfer. In addition, we advocate for a rigorous examination of the evidence for the localization of α-synuclein in extracellular vesicles.
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Affiliation(s)
| | - Randy W. Schekman
- Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, CA, United States
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42
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So RWL, Amano G, Stuart E, Ebrahim Amini A, Aguzzi A, Collingridge GL, Watts JC. α-Synuclein strain propagation is independent of cellular prion protein expression in a transgenic synucleinopathy mouse model. PLoS Pathog 2024; 20:e1012517. [PMID: 39264912 PMCID: PMC11392418 DOI: 10.1371/journal.ppat.1012517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 08/20/2024] [Indexed: 09/14/2024] Open
Abstract
The cellular prion protein, PrPC, has been postulated to function as a receptor for α-synuclein, potentially facilitating cell-to-cell spreading and/or toxicity of α-synuclein aggregates in neurodegenerative disorders such as Parkinson's disease. Previously, we generated the "Salt (S)" and "No Salt (NS)" strains of α-synuclein aggregates that cause distinct pathological phenotypes in M83 transgenic mice overexpressing A53T-mutant human α-synuclein. To test the hypothesis that PrPC facilitates the propagation of α-synuclein aggregates, we produced M83 mice that either express or do not express PrPC. Following intracerebral inoculation with the S or NS strain, the absence of PrPC in M83 mice did not prevent disease development and had minimal influence on α-synuclein strain-specified attributes such as the extent of cerebral α-synuclein deposition, selective targeting of specific brain regions and cell types, the morphology of induced α-synuclein deposits, and the structural fingerprints of protease-resistant α-synuclein aggregates. Likewise, there were no appreciable differences in disease manifestation between PrPC-expressing and PrPC-lacking M83 mice following intraperitoneal inoculation of the S strain. Interestingly, intraperitoneal inoculation with the NS strain resulted in two distinct disease phenotypes, indicative of α-synuclein strain evolution, but this was also independent of PrPC expression. Overall, these results suggest that PrPC plays at most a minor role in the propagation, neuroinvasion, and evolution of α-synuclein strains in mice that express A53T-mutant human α-synuclein. Thus, other putative receptors or cell-to-cell propagation mechanisms may have a larger effect on the spread of α-synuclein aggregates during disease.
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Affiliation(s)
- Raphaella W L So
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
- Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Genki Amano
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Erica Stuart
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
| | - Aeen Ebrahim Amini
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Adriano Aguzzi
- Institute of Neuropathology, University of Zurich, Zurich, Switzerland
| | - Graham L Collingridge
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
- Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Joel C Watts
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada
- Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
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43
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Kamano S, Ozawa D, Ikenaka K, Nagai Y. Role of Lipids in the Pathogenesis of Parkinson's Disease. Int J Mol Sci 2024; 25:8935. [PMID: 39201619 PMCID: PMC11354291 DOI: 10.3390/ijms25168935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/07/2024] [Accepted: 08/10/2024] [Indexed: 09/02/2024] Open
Abstract
Aggregation of α-synuclein (αSyn) and its accumulation as Lewy bodies play a central role in the pathogenesis of Parkinson's disease (PD). However, the mechanism by which αSyn aggregates in the brain remains unclear. Biochemical studies have demonstrated that αSyn interacts with lipids, and these interactions affect the aggregation process of αSyn. Furthermore, genetic studies have identified mutations in lipid metabolism-associated genes such as glucocerebrosidase 1 (GBA1) and synaptojanin 1 (SYNJ1) in sporadic and familial forms of PD, respectively. In this review, we focus on the role of lipids in triggering αSyn aggregation in the pathogenesis of PD and propose the possibility of modulating the interaction of lipids with αSyn as a potential therapy for PD.
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Grants
- 24H00630 Ministry of Education, Culture, Sports, Science and Technology
- 21H02840 Ministry of Education, Culture, Sports, Science and Technology
- 17K19658 Ministry of Education, Culture, Sports, Science and Technology
- 20H05927 Ministry of Education, Culture, Sports, Science and Technology
- JP16ek0109018 Japan Agency for Medical Research and Development
- JP19ek0109222 Japan Agency for Medical Research and Development
- 30-3 National Center of Neurology and Psychiatry
- 30-9 National Center of Neurology and Psychiatry
- 3-9 National Center of Neurology and Psychiatry
- 6-9 National Center of Neurology and Psychiatry
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Affiliation(s)
- Shumpei Kamano
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
| | - Daisaku Ozawa
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
| | - Kensuke Ikenaka
- Department of Neurology, Osaka University Graduate School of Medicine, Suita 565-0871, Osaka, Japan;
| | - Yoshitaka Nagai
- Department of Neurology, Kindai University Faculty of Medicine, Osaka-Sayama 589-8511, Osaka, Japan; (S.K.); (D.O.)
- Life Science Research Institute, Kindai University, Osaka-Sayama 589-8511, Osaka, Japan
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44
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Saitoh Y, Mizusawa H. Prion diseases, always a threat? J Neurol Sci 2024; 463:123119. [PMID: 39029285 DOI: 10.1016/j.jns.2024.123119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/21/2024]
Abstract
Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an "archetype of various neurodegenerative diseases". Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.
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Affiliation(s)
- Yuji Saitoh
- Department of Neurology, Tokyo Metropolitan Neurological Hospital, 2-6-1 Musashidai, Fuchu, Tokyo 183-0042, Japan
| | - Hidehiro Mizusawa
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo 187-8551, Japan.
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45
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Leak RK, Clark RN, Abbas M, Xu F, Brodsky JL, Chen J, Hu X, Luk KC. Current insights and assumptions on α-synuclein in Lewy body disease. Acta Neuropathol 2024; 148:18. [PMID: 39141121 PMCID: PMC11324801 DOI: 10.1007/s00401-024-02781-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Revised: 07/28/2024] [Accepted: 08/04/2024] [Indexed: 08/15/2024]
Abstract
Lewy body disorders are heterogeneous neurological conditions defined by intracellular inclusions composed of misshapen α-synuclein protein aggregates. Although α-synuclein aggregates are only one component of inclusions and not strictly coupled to neurodegeneration, evidence suggests they seed the propagation of Lewy pathology within and across cells. Genetic mutations, genomic multiplications, and sequence polymorphisms of the gene encoding α-synuclein are also causally linked to Lewy body disease. In nonfamilial cases of Lewy body disease, the disease trigger remains unidentified but may range from industrial/agricultural toxicants and natural sources of poisons to microbial pathogens. Perhaps due to these peripheral exposures, Lewy inclusions appear at early disease stages in brain regions connected with cranial nerves I and X, which interface with inhaled and ingested environmental elements in the nasal or gastrointestinal cavities. Irrespective of its identity, a stealthy disease trigger most likely shifts soluble α-synuclein (directly or indirectly) into insoluble, cross-β-sheet aggregates. Indeed, β-sheet-rich self-replicating α-synuclein multimers reside in patient plasma, cerebrospinal fluid, and other tissues, and can be subjected to α-synuclein seed amplification assays. Thus, clinicians should be able to capitalize on α-synuclein seed amplification assays to stratify patients into potential responders versus non-responders in future clinical trials of α-synuclein targeted therapies. Here, we briefly review the current understanding of α-synuclein in Lewy body disease and speculate on pathophysiological processes underlying the potential transmission of α-synucleinopathy across the neuraxis.
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Affiliation(s)
- Rehana K Leak
- Graduate School of Pharmaceutical Sciences, Duquesne University, 418C Mellon Hall, 913 Bluff Street, Pittsburgh, PA, 15219, USA.
| | - Rachel N Clark
- Graduate School of Pharmaceutical Sciences, Duquesne University, 418C Mellon Hall, 913 Bluff Street, Pittsburgh, PA, 15219, USA
| | - Muslim Abbas
- Graduate School of Pharmaceutical Sciences, Duquesne University, 418C Mellon Hall, 913 Bluff Street, Pittsburgh, PA, 15219, USA
| | - Fei Xu
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jeffrey L Brodsky
- Department of Biological Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jun Chen
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
- Geriatric Research, Education and Clinical Center, Veterans Affairs Pittsburgh Health Care System, Pittsburgh, Pennsylvania, USA
| | - Xiaoming Hu
- Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kelvin C Luk
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Pennsylvania, PA, USA
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46
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Chen L, Chehade HD, Chu HY. Motor Cortical Neuronal Hyperexcitability Associated with α-Synuclein Aggregation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.24.604995. [PMID: 39091827 PMCID: PMC11291145 DOI: 10.1101/2024.07.24.604995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/04/2024]
Abstract
Dysfunction of the cerebral cortex is thought to underlie motor and cognitive impairments in Parkinson disease (PD). While cortical function is known to be suppressed by abnormal basal ganglia output following dopaminergic degeneration, it remains to be determined how the deposition of Lewy pathology disrupts cortical circuit integrity and function. Moreover, it is also unknown whether cortical Lewy pathology and midbrain dopaminergic degeneration interact to disrupt cortical function in late-stage. To begin to address these questions, we injected α-synuclein (αSyn) preformed fibrils (PFFs) into the dorsolateral striatum of mice to seed αSyn pathology in the cortical cortex and induce degeneration of midbrain dopaminergic neurons. Using this model system, we reported that αSyn aggregates accumulate in the motor cortex in a layer- and cell-subtype-specific pattern. Particularly, intratelencephalic neurons (ITNs) showed earlier accumulation and greater extent of αSyn aggregates relative to corticospinal neurons (CSNs). Moreover, we demonstrated that the intrinsic excitability and inputs resistance of αSyn aggregates-bearing ITNs in the secondary motor cortex (M2) are increased, along with a noticeable shrinkage of cell bodies and loss of dendritic spines. Last, neither the intrinsic excitability of CSNs nor their thalamocortical input was altered by a partial striatal dopamine depletion associated with αSyn pathology. Our results documented motor cortical neuronal hyperexcitability associated with αSyn aggregation and provided a novel mechanistic understanding of cortical circuit dysfunction in PD.
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Affiliation(s)
- Liqiang Chen
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, United States
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, United States
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington DC, 20007, United States
| | - Hiba Douja Chehade
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, United States
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, United States
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington DC, 20007, United States
| | - Hong-Yuan Chu
- Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, 20852, United States
- Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, United States
- Department of Pharmacology and Physiology, Georgetown University of Medical Center, Washington DC, 20007, United States
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47
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Zampar S, Di Gregorio SE, Grimmer G, Watts JC, Ingelsson M. "Prion-like" seeding and propagation of oligomeric protein assemblies in neurodegenerative disorders. Front Neurosci 2024; 18:1436262. [PMID: 39161653 PMCID: PMC11330897 DOI: 10.3389/fnins.2024.1436262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/17/2024] [Indexed: 08/21/2024] Open
Abstract
Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-β fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how α-synuclein, amyloid-β, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.
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Affiliation(s)
- Silvia Zampar
- Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Sonja E. Di Gregorio
- Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Gustavo Grimmer
- Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
| | - Joel C. Watts
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
- Department of Biochemistry, University of Toronto, Toronto, ON, Canada
| | - Martin Ingelsson
- Krembil Brain Institute, University Health Network, Toronto, ON, Canada
- Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Public Health/Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
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48
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Tullo S, Miranda AS, Del Cid-Pellitero E, Lim MP, Gallino D, Attaran A, Patel R, Novikov V, Park M, Beraldo FH, Luo W, Shlaifer I, Durcan TM, Bussey TJ, Saksida LM, Fon EA, Prado VF, Prado MAM, Chakravarty MM. Neuroanatomical and cognitive biomarkers of alpha-synuclein propagation in a mouse model of synucleinopathy prior to onset of motor symptoms. J Neurochem 2024; 168:1546-1564. [PMID: 37804203 DOI: 10.1111/jnc.15967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 08/31/2023] [Accepted: 09/11/2023] [Indexed: 10/09/2023]
Abstract
Significant evidence suggests that misfolded alpha-synuclein (aSyn), a major component of Lewy bodies, propagates in a prion-like manner contributing to disease progression in Parkinson's disease (PD) and other synucleinopathies. In fact, timed inoculation of M83 hemizygous mice with recombinant human aSyn preformed fibrils (PFF) has shown symptomatic deficits after substantial spreading of pathogenic alpha-synuclein, as detected by markers for the phosphorylation of S129 of aSyn. However, whether accumulated toxicity impact human-relevant cognitive and structural neuroanatomical measures is not fully understood. Here we performed a single unilateral striatal PFF injection in M83 hemizygous mice, and using two assays with translational potential, ex vivo magnetic resonance imaging (MRI) and touchscreen testing, we examined the combined neuroanatomical and behavioral impact of aSyn propagation. In PFF-injected mice, we observed widespread atrophy in bilateral regions that project to or receive input from the injection site using MRI. We also identified early deficits in reversal learning prior to the emergence of motor symptoms. Our findings highlight a network of regions with related cellular correlates of pathology that follow the progression of aSyn spreading, and that affect brain areas relevant for reversal learning. Our experiments suggest that M83 hemizygous mice injected with human PFF provides a model to understand how misfolded aSyn affects human-relevant pre-clinical measures and suggest that these pre-clinical biomarkers could be used to detect early toxicity of aSyn and provide better translational measures between mice and human disease.
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Affiliation(s)
- Stephanie Tullo
- Integrated Program in Neuroscience, McGill University, Montreal, Quebec, Canada
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Aline S Miranda
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Departamento de Morfologia, Instituto de Ciencias Biologicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Esther Del Cid-Pellitero
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Mei Peng Lim
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Daniel Gallino
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Anoosha Attaran
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Raihaan Patel
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
- Department of Biological & Biomedical Engineering, McGill University, Montreal, Quebec, Canada
| | - Vladislav Novikov
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Megan Park
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
| | - Flavio H Beraldo
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Wen Luo
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Irina Shlaifer
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada
| | - Timothy J Bussey
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Lisa M Saksida
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Edward A Fon
- McGill Parkinson Program, Neurodegenerative Diseases Group, Department of Neurology and Neurosurgery, Montreal Neurological Institute-Hospital, McGill University, Montreal, Quebec, Canada
| | - Vania F Prado
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - Marco A M Prado
- Robarts Research Institute, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
- Department of Anatomy & Cell Biology, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada
| | - M Mallar Chakravarty
- Computational Brain Anatomy (CoBrA) Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, McGill University, Verdun, Quebec, Canada
- Department of Biological & Biomedical Engineering, McGill University, Montreal, Quebec, Canada
- Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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49
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Dadgar-Kiani E, Bieri G, Melki R, Hossain A, Gitler AD, Lee JH. Neuromodulation modifies α-synuclein spreading dynamics in vivo and the pattern is predicted by changes in whole-brain function. Brain Stimul 2024; 17:938-946. [PMID: 39096960 PMCID: PMC11416857 DOI: 10.1016/j.brs.2024.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/08/2024] [Accepted: 07/31/2024] [Indexed: 08/05/2024] Open
Abstract
BACKGROUND Many neurodegenerative disease treatments, such as deep brain stimulation for Parkinson's Disease, can alleviate symptoms by primarily compensating for circuit dysfunctions. However, the stimulation's effect on the underlying disease progression remains relatively unknown. Here, we report that neuromodulation can not only modulate circuit function but also modulate the in vivo spreading dynamics of α-synuclein pathology, the primary pathological hallmark observed in Parkinson's Disease. METHODS In a mouse model, pre-formed fibrils were injected into the striatum to induce widespread α-synuclein pathology. Two days after fibril injection, mice were treated for two weeks with daily optogenetic stimulation of the Secondary Motor Area, Layer V. Whole brains were then extracted, immunolabeled, cleared, and imaged with light-sheet fluorescent microscopy. RESULTS Repeated optogenetic stimulation led to a decrease in pathology at the site of stimulation and at various cortical and subcortical regions, while the contralateral cortex saw a consistent increase. Aligning the pathology changes with optogenetic-fMRI measured brain activity, we found that the changes in pathology and brain function had similar spatial locations but opposite polarity. CONCLUSION These results demonstrate the ability to modulate and predict whole brain pathology changes using neuromodulation, opening a new horizon for investigating optimized neuromodulation therapies.
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Affiliation(s)
- Ehsan Dadgar-Kiani
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA
| | - Gregor Bieri
- Department of Genetics, Stanford University, CA, 94305, USA
| | - Ronald Melki
- Institut François Jacob, MIRCen, CEA and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France
| | - Aronee Hossain
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA
| | - Aaron D Gitler
- Department of Genetics, Stanford University, CA, 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA, 94158, USA
| | - Jin Hyung Lee
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA; Department of Electrical Engineering, Stanford University, CA, 94305, USA; Department of Neurosurgery, Stanford University, Stanford, CA, 94305, USA.
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Park TY, Jeon J, Cha Y, Kim KS. Past, present, and future of cell replacement therapy for parkinson's disease: a novel emphasis on host immune responses. Cell Res 2024; 34:479-492. [PMID: 38777859 PMCID: PMC11217403 DOI: 10.1038/s41422-024-00971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 04/28/2024] [Indexed: 05/25/2024] Open
Abstract
Parkinson's disease (PD) stands as the second most common neurodegenerative disorder after Alzheimer's disease, and its prevalence continues to rise with the aging global population. Central to the pathophysiology of PD is the specific degeneration of midbrain dopamine neurons (mDANs) in the substantia nigra. Consequently, cell replacement therapy (CRT) has emerged as a promising treatment approach, initially supported by various open-label clinical studies employing fetal ventral mesencephalic (fVM) cells. Despite the initial favorable results, fVM cell therapy has intrinsic and logistical limitations that hinder its transition to a standard treatment for PD. Recent efforts in the field of cell therapy have shifted its focus towards the utilization of human pluripotent stem cells, including human embryonic stem cells and induced pluripotent stem cells, to surmount existing challenges. However, regardless of the transplantable cell sources (e.g., xenogeneic, allogeneic, or autologous), the poor and variable survival of implanted dopamine cells remains a major obstacle. Emerging evidence highlights the pivotal role of host immune responses following transplantation in influencing the survival of implanted mDANs, underscoring an important area for further research. In this comprehensive review, building upon insights derived from previous fVM transplantation studies, we delve into the functional ramifications of host immune responses on the survival and efficacy of grafted dopamine cells. Furthermore, we explore potential strategic approaches to modulate the host immune response, ultimately aiming for optimal outcomes in future clinical applications of CRT for PD.
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Affiliation(s)
- Tae-Yoon Park
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Jeha Jeon
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Young Cha
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA
| | - Kwang-Soo Kim
- Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, Belmont, MA, USA.
- Program in Neuroscience, Harvard Medical School, Belmont, MA, USA.
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
- Harvard Stem Cell Institute, Harvard Medical School, Belmont, MA, USA.
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