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1
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Buneeva O, Medvedev A. Monoamine Oxidase Inhibitors in Toxic Models of Parkinsonism. Int J Mol Sci 2025; 26:1248. [PMID: 39941014 PMCID: PMC11818313 DOI: 10.3390/ijms26031248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 02/16/2025] Open
Abstract
Monoamine oxidase inhibitors are widely used for the symptomatic treatment of Parkinson's disease (PD). They demonstrate antiparkinsonian activity in different toxin-based models induced by 6-hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and pesticides (rotenone and paraquat). In some models, such as MPTP-induced PD, MAO inhibitors prevent the formation of the neurotoxin MPP+ from the protoxin MPTP. Regardless of the toxin's nature, potent MAO inhibitors prevent dopamine loss reduction, the formation of hydrogen peroxide, hydrogen peroxide signaling, and the accumulation of hydrogen peroxide-derived reactive oxygen species responsible for the development of oxidative stress. It becomes increasingly clear that some metabolites of MAO inhibitors (e.g., the rasagiline metabolite 1-R-aminoindan) possess their own bio-pharmacological activities unrelated to the parent compound. In addition, various MAO inhibitors exhibit multitarget action, in which MAO-independent effects prevail. This opens new prospects in the development of novel therapeutics based on simultaneous actions on several prospective targets for the therapy of PD.
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Affiliation(s)
| | - Alexei Medvedev
- Institute of Biomedical Chemistry, 10 Pogodinskaya Street, 119121 Moscow, Russia;
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2
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Zhao Z, Song X, Wang Y, Yu L, Huang G, Li Y, Zong R, Liu T, Ji Q, Zheng Y, Liu B, Zhu Q, Chen L, Gao C, Liu H. E3 ubiquitin ligase TRIM31 alleviates dopaminergic neurodegeneration by promoting proteasomal degradation of VDAC1 in Parkinson's Disease model. Cell Death Differ 2024; 31:1410-1421. [PMID: 38918620 PMCID: PMC11519394 DOI: 10.1038/s41418-024-01334-1] [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: 07/11/2023] [Revised: 06/14/2024] [Accepted: 06/18/2024] [Indexed: 06/27/2024] Open
Abstract
Mitochondrial dysfunction plays a pivotal role in the pathogenesis of Parkinson's disease (PD). As a mitochondrial governor, voltage-dependent anion channel 1 (VDAC1) is critical for cell survival and death signals and implicated in neurodegenerative diseases. However, the mechanisms of VDAC1 regulation are poorly understood and the role of tripartite motif-containing protein 31 (TRIM31), an E3 ubiquitin ligase which is enriched in mitochondria, in PD remains unclear. In this study, we found that TRIM31-/- mice developed age associated motor defects and dopaminergic (DA) neurodegeneration spontaneously. In addition, TRIM31 was markedly reduced both in nigrostriatal region of PD mice induced by MPTP and in SH-SY5Y cells stimulated by MPP+. TRIM31 deficiency significantly aggravated DA neurotoxicity induced by MPTP. Mechanistically, TRIM31 interacted with VDAC1 and catalyzed the K48-linked polyubiquitination to degrade it through its E3 ubiquitin ligase activity. In conclusion, we demonstrated for the first time that TRIM31 served as an important regulator in DA neuronal homeostasis by facilitating VDAC1 degradation through the ubiquitin-proteasome pathway. Our study identified TRIM31 as a novel potential therapeutic target and pharmaceutical intervention to the interaction between TRIM31 and VDAC1 may provide a promising strategy for PD.
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Affiliation(s)
- Ze Zhao
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Xiaomeng Song
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Yimeng Wang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Lu Yu
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Gan Huang
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Yiquan Li
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Runzhe Zong
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Tengfei Liu
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Qiuran Ji
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China
| | - Yi Zheng
- Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Bingyu Liu
- Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, PR China
| | - Qingfen Zhu
- Shandong Institute for Food and Drug Control, Jinan, Shandong, PR China
| | - Lin Chen
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China.
| | - Chengjiang Gao
- Key Laboratory of Infection and Immunity of Shandong Province & Department of Immunology, School of Basic Medical Sciences, Shandong University, Jinan, PR China.
| | - Huiqing Liu
- Department of Pharmacology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, PR China.
- Department of Rehabilitation Medicine, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, PR China.
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3
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Grotemeyer A, Petschner T, Peach R, Hoehl D, Knauer T, Thomas U, Endres H, Blum R, Sendtner M, Volkmann J, Ip CW. Standardized wireless deep brain stimulation system for mice. NPJ Parkinsons Dis 2024; 10:153. [PMID: 39143106 PMCID: PMC11324748 DOI: 10.1038/s41531-024-00767-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 07/29/2024] [Indexed: 08/16/2024] Open
Abstract
Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson's disease-like and DBS-induced gait changes.
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Affiliation(s)
- Alexander Grotemeyer
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Tobias Petschner
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Robert Peach
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
- Department of Brain Sciences, Imperial College London, Du Cane Road, London, W12 0NN, UK
| | - Dirk Hoehl
- Thomas RECORDING GmbH, Winchester Straße 8, 35394, Giessen, Germany
| | - Torsten Knauer
- Thomas RECORDING GmbH, Winchester Straße 8, 35394, Giessen, Germany
| | - Uwe Thomas
- Thomas RECORDING GmbH, Winchester Straße 8, 35394, Giessen, Germany
| | - Heinz Endres
- University of Applied Science Würzburg-Schweinfurt, Ignaz-Schön-Straße 11, 97421, Schweinfurt, Germany
| | - Robert Blum
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Michael Sendtner
- Institute of Clinical Neurobiology, University Hospital of Würzburg, Versbacherstraße 5, 97078, Würzburg, Germany
| | - Jens Volkmann
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany
| | - Chi Wang Ip
- Department of Neurology, University Hospital of Würzburg, Josef-Schneider-Straße 11, 97080, Würzburg, Germany.
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4
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Dakik H, Mantash S, Nehme A, Kobeissy F, Zabet-Moghaddam M, Mirzaei P, Mechref Y, Gaillard A, Prestoz L, Zibara K. Analysis of the Neuroproteome Associated With Cell Therapy After Intranigral Grafting in a Mouse Model of Parkinson Disease. Front Neurosci 2021; 15:621121. [PMID: 33776636 PMCID: PMC7991918 DOI: 10.3389/fnins.2021.621121] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Accepted: 02/09/2021] [Indexed: 12/04/2022] Open
Abstract
Advances in large-scale proteomics analysis have been very useful in understanding pathogenesis of diseases and elaborating therapeutic strategies. Proteomics has been employed to study Parkinson disease (PD); however, sparse studies reported proteome investigation after cell therapy approaches. In this study, we used liquid chromatography–tandem mass spectrometry and systems biology to identify differentially expressed proteins in a translational mouse model of PD after cell therapy. Proteins were extracted from five nigrostriatal-related brain regions of mice previously lesioned with 6-hydroxydopamine in the substantia nigra. Protein expression was compared in non-grafted brain to 1 and 7 days after intranigral grafting of E12.5 embryonic ventral mesencephalon (VM). We found a total of 277 deregulated proteins after transplantation, which are enriched for lipid metabolism, oxidative phosphorylation and PD, thus confirming that our animal model is similar to human PD and that the presence of grafted cells modulates the expression of these proteins. Notably, seven proteins (Acta1, Atp6v1e1, Eci3, Lypla2, Pip4k2a, Sccpdh, and Sh3gl2) were commonly down-regulated after engraftment in all studied brain regions. These proteins are known to be involved in the formation of lipids and recycling of dopamine (DA) vesicle at the synapse. Moreover, intranigral transplantation of VM cells decreased the expression of proteins related to oxidative stress, especially in the nigrostriatal pathway containing the DA grafted neurons. In the same regions, an up-regulation of several proteins including α-synuclein and tyrosine hydroxylase was observed, whereas expression of tetraspanin 7 was shut down. Overall, these results suggest that intranigral transplantation of VM tissue in an animal model of PD may induce a decrease of oxidative stress in the nigrostriatal pathway and a restoration of the machinery of neurotransmitters, particularly DA release to promote DA transmission through a decrease of D2 DA receptors endocytosis. Identification of new mechanistic elements involved in the nigrostriatal reconstruction process, using translational animal models and systems biology, is a promising approach to enhance the repair of this pathway in PD patients undergoing cell therapy.
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Affiliation(s)
- Hassan Dakik
- ER045, PRASE, Lebanese University, Beirut, Lebanon.,Université de Tours, Tours, France
| | - Sarah Mantash
- ER045, PRASE, Lebanese University, Beirut, Lebanon.,INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France
| | - Ali Nehme
- ER045, PRASE, Lebanese University, Beirut, Lebanon.,McGill University and Génome Québec Innovation Centre, McGill University, Montreal, QC, Canada
| | - Firas Kobeissy
- Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Masoud Zabet-Moghaddam
- Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX, United States
| | - Parvin Mirzaei
- Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX, United States
| | - Yehia Mechref
- Center for Biotechnology and Genomics, Texas Tech University, Lubbock, TX, United States
| | - Afsaneh Gaillard
- INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France
| | - Laetitia Prestoz
- INSERM, Laboratoire de Neurosciences Expérimentales et Cliniques, Université de Poitiers, Poitiers, France
| | - Kazem Zibara
- ER045, PRASE, Lebanese University, Beirut, Lebanon.,Department of Biology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon
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5
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Wang B, Huang M, Shang D, Yan X, Zhao B, Zhang X. Mitochondrial Behavior in Axon Degeneration and Regeneration. Front Aging Neurosci 2021; 13:650038. [PMID: 33762926 PMCID: PMC7982458 DOI: 10.3389/fnagi.2021.650038] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 02/18/2021] [Indexed: 12/19/2022] Open
Abstract
Mitochondria are organelles responsible for bioenergetic metabolism, calcium homeostasis, and signal transmission essential for neurons due to their high energy consumption. Accumulating evidence has demonstrated that mitochondria play a key role in axon degeneration and regeneration under physiological and pathological conditions. Mitochondrial dysfunction occurs at an early stage of axon degeneration and involves oxidative stress, energy deficiency, imbalance of mitochondrial dynamics, defects in mitochondrial transport, and mitophagy dysregulation. The restoration of these defective mitochondria by enhancing mitochondrial transport, clearance of reactive oxidative species (ROS), and improving bioenergetic can greatly contribute to axon regeneration. In this paper, we focus on the biological behavior of axonal mitochondria in aging, injury (e.g., traumatic brain and spinal cord injury), and neurodegenerative diseases (Alzheimer's disease, AD; Parkinson's disease, PD; Amyotrophic lateral sclerosis, ALS) and consider the role of mitochondria in axon regeneration. We also compare the behavior of mitochondria in different diseases and outline novel therapeutic strategies for addressing abnormal mitochondrial biological behavior to promote axonal regeneration in neurological diseases and injuries.
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Affiliation(s)
- Biyao Wang
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Minghao Huang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Dehao Shang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xu Yan
- The VIP Department, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Baohong Zhao
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
| | - Xinwen Zhang
- Center of Implant Dentistry, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China
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6
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Joaquim HPG, Costa AC, Serpa MH, Talib LL, Gattaz WF. Reduced Annexin A3 in schizophrenia. Eur Arch Psychiatry Clin Neurosci 2020; 270:489-494. [PMID: 31372726 DOI: 10.1007/s00406-019-01048-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/23/2019] [Indexed: 12/17/2022]
Abstract
The cellular and molecular mechanisms underlying onset and development of schizophrenia have not yet been completely elucidated, but the association of disturbed neuroplasticity and inflammation has gained particular relevance recently. These mechanisms are linked to annexins functions. ANXA3, particularly, is associated to inflammation and membrane metabolism cascades. The aim was to determine the ANXA3 levels in first-onset drug-naïve psychotic patients. We investigated by western blot the protein expression of annexin A3 in platelets of first-onset, drug-naïve psychotic patients (diagnoses according to DSM-IV: 28 schizophrenia, 27 bipolar disorder) as compared to 30 age- and gender-matched healthy controls. Annexin A3 level was lower in schizophrenia patients as compared to healthy controls (p < 0.001) and to bipolar patients (p < 0.001). Twenty out of 28 schizophrenic patients had undetectable annexin A3 levels, as compared to none from the bipolar and none from the control subjects. ANXA3 was reduced in drug-naïve patients with schizophrenia. ANXA3 affects neuroplasticity, inflammation and apoptosis, as well as it modulates membrane phospholipid metabolism. All these processes have been discussed in regard to the biology of schizophrenia. In face of these data, we feel that further studies with larger samples are warranted to investigate the possible role of reduced ANXA3 as a possible risk marker for schizophrenia.
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Affiliation(s)
- Helena P G Joaquim
- Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos, 785, 3º andar, São Paulo, SP, 05403-010, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, São Paulo, Brazil
| | - Alana Caroline Costa
- Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos, 785, 3º andar, São Paulo, SP, 05403-010, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, São Paulo, Brazil
| | - Maurício Henriques Serpa
- Laboratory of Psychiatric Neuroimaging (LIM-21), Department and Institute of Psychiatry, University of Sao Paulo Medical School, São Paulo, Brazil
| | - Leda L Talib
- Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos, 785, 3º andar, São Paulo, SP, 05403-010, Brazil.,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, São Paulo, Brazil
| | - Wagner F Gattaz
- Laboratory of Neuroscience (LIM-27), Department and Institute of Psychiatry, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos, 785, 3º andar, São Paulo, SP, 05403-010, Brazil. .,Instituto Nacional de Biomarcadores em Neuropsiquiatria (INBioN), Conselho Nacional de Desenvolvimento Cientifico e Tecnológico, São Paulo, Brazil.
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7
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Lam I, Hallacli E, Khurana V. Proteome-Scale Mapping of Perturbed Proteostasis in Living Cells. Cold Spring Harb Perspect Biol 2020; 12:cshperspect.a034124. [PMID: 30910772 DOI: 10.1101/cshperspect.a034124] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Proteinopathies are degenerative diseases in which specific proteins adopt deleterious conformations, leading to the dysfunction and demise of distinct cell types. They comprise some of the most significant diseases of aging-from Alzheimer's disease to Parkinson's disease to type 2 diabetes-for which not a single disease-modifying or preventative strategy exists. Here, we survey approaches in tractable cellular and organismal models that bring us toward a more complete understanding of the molecular consequences of protein misfolding. These include proteome-scale profiling of genetic modifiers, as well as transcriptional and proteome changes. We describe assays that can capture protein interactomes in situ and distinct protein conformational states. A picture of cellular drivers and responders to proteotoxicity emerges from this work, distinguishing general alterations of proteostasis from cellular events that are deeply tied to the intrinsic function of the misfolding protein. These distinctions have consequences for the understanding and treatment of proteinopathies.
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Affiliation(s)
- Isabel Lam
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Erinc Hallacli
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
| | - Vikram Khurana
- Ann Romney Center for Neurologic Disease, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.,Harvard Stem Cell Institute, Cambridge, Massachusetts 02138.,New York Stem Cell Foundation - Robertson Investigator
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8
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Gong SN, Zhu JP, Ma YJ, Zhao DQ. Proteomics of the mediodorsal thalamic nucleus of rats with stress-induced gastric ulcer. World J Gastroenterol 2019; 25:2911-2923. [PMID: 31249449 PMCID: PMC6589736 DOI: 10.3748/wjg.v25.i23.2911] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Revised: 05/08/2019] [Accepted: 05/18/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Stress-induced gastric ulcer (SGU) is one of the most common visceral complications after trauma. Restraint water-immersion stress (RWIS) can cause serious gastrointestinal dysfunction and has been widely used to study the pathogenesis of SGU to identify medications that can cure the disease. The mediodorsal thalamic nucleus (MD) is the centre integrating visceral and physical activity and contributes to SGU induced by RWIS. Hence, the role of the MD during RWIS needs to be studied.
AIM To screen for differentially expressed proteins in the MD of the RWIS rats to further elucidate molecular mechanisms of SGU.
METHODS Male Wistar rats were selected randomly and divided into two groups, namely, a control group and an RWIS group. Gastric mucosal lesions of the sacrificed rats were measured using the erosion index and the proteomic profiles of the MD were generated through isobaric tags for relative and absolute quantitation (iTRAQ) coupled with two-dimensional liquid chromatography and tandem mass spectrometry. Additionally, iTRAQ results were verified by Western blot analysis.
RESULTS A total of 2853 proteins were identified, and these included 65 dysregulated (31 upregulated and 34 downregulated) proteins (fold change ratio ≥ 1.2). Gene Ontology (GO) analysis showed that most of the upregulated proteins are primarily related to cell division, whereas most of the downregulated proteins are related to neuron morphogenesis and neurotransmitter regulation. Ingenuity Pathway Analysis revealed that the dysregulated proteins are mainly involved in the neurological disease signalling pathways. Furthermore, our results indicated that glycogen synthase kinase-3 beta might be related to the central mechanism through which RWIS gives rise to SGU.
CONCLUSION Quantitative proteomic analysis elucidated the molecular targets associated with the production of SGU and provides insights into the role of the MD. The underlying molecular mechanisms need to be further dissected.
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Affiliation(s)
- Sheng-Nan Gong
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Jian-Ping Zhu
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Ying-Jie Ma
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
| | - Dong-Qin Zhao
- College of Life Sciences, Shandong Normal University, Jinan 250014, Shandong Province, China
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9
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Postu PA, Ion L, Drochioiu G, Petre BA, Glocker MO. Mass spectrometric characterization of the zein protein composition in maize flour extracts upon protein separation by SDS-PAGE and 2D gel electrophoresis. Electrophoresis 2019; 40:2747-2758. [PMID: 31169923 DOI: 10.1002/elps.201900108] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 05/23/2019] [Accepted: 05/27/2019] [Indexed: 12/24/2022]
Abstract
Highly homogenous α zein protein was isolated from maize kernels in an environment-friendly process using 95% ethanol as solvent. Due to the polyploidy and genetic polymorphism of the plant source, the application of high resolution separation methods in conjunction with precise analytical methods, such as MALDI-TOF-MS, is required to accurately estimate homogeneity of products that contain natural zein protein. The α zein protein product revealed two main bands in SDS-PAGE analysis, one at 25 kDa and other at 20 kDa apparent molecular mass. Yet, high resolution 2DE revealed approximately five protein spot groups in each row, the first at ca. 25 kDa and the second at ca. 20 kDa. Peptide mass fingerprinting data of the proteins in the two dominant SDS-PAGE bands matched to 30 amino acid sequence entries out of 102 non-redundant data base entries. MALDI-TOF-MS peptide mapping of the proteins from all spots indicated the presence of only α zein proteins. The most prominent ion signals in the MALDI mass spectra of the protein mixture of the 25 kDa SDS gel band after in-gel digestion were found at m/z 1272.6 and m/z 2009.1, and the most prominent ion signals of the protein mixture of the 20 kDa band after in-gel digestion were recorded at m/z 1083.5 and m/z 1691.8. These ion signals have been found typical for α zein proteins and may serve as marker ion signals which upon chymotryptic digestion reliably indicate the presence of α zein protein in two hybrid corn products.
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Affiliation(s)
- Paula A Postu
- Department of Biology, Alexandru Ioan Cuza University, Iasi, Romania.,Transcend Research Center - Regional Institute of Oncology, Iasi, Romania
| | - Laura Ion
- Department of Chemistry, Alexandru Ioan Cuza University, Iasi, Romania
| | - Gabi Drochioiu
- Department of Chemistry, Alexandru Ioan Cuza University, Iasi, Romania
| | - Brindusa A Petre
- Transcend Research Center - Regional Institute of Oncology, Iasi, Romania.,Department of Chemistry, Alexandru Ioan Cuza University, Iasi, Romania
| | - Michael O Glocker
- Proteome Center Rostock, Medical Faculty and Natural Science Faculty, University of Rostock, Rostock, Germany
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10
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Proteome analysis reveals that de novo regenerated mucosa over fibula flap-reconstructed mandibles resembles mature keratinized oral mucosa. Oral Oncol 2018; 78:207-215. [DOI: 10.1016/j.oraloncology.2018.01.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 01/15/2018] [Accepted: 01/23/2018] [Indexed: 01/30/2023]
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11
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Shah A, Schiffmacher AT, Taneyhill LA. Annexin A6 controls neuronal membrane dynamics throughout chick cranial sensory gangliogenesis. Dev Biol 2017; 425:85-99. [PMID: 28315296 DOI: 10.1016/j.ydbio.2017.03.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 03/10/2017] [Accepted: 03/11/2017] [Indexed: 12/19/2022]
Abstract
Cranial sensory ganglia are components of the peripheral nervous system that possess a significant somatosensory role and include neurons within the trigeminal and epibranchial nerve bundles. Although it is well established that these ganglia arise from interactions between neural crest and neurogenic placode cells, the molecular basis of ganglia assembly is still poorly understood. Members of the Annexin protein superfamily play key roles in sensory nervous system development throughout metazoans. Annexin A6 is expressed in chick trigeminal and epibranchial placode cell-derived neuroblasts and neurons, but its function in cranial ganglia formation has not been elucidated. To this end, we interrogated the role of Annexin A6 using gene perturbation studies in the chick embryo. Our data reveal that placode cell-derived neuroblasts with reduced Annexin A6 levels ingress and migrate normally to the ganglionic anlage, where neural crest cell corridors correctly form around them. Strikingly, while Annexin A6-depleted placode cell-derived neurons still express mature neuronal markers, they fail to form two long processes, which are considered morphological features of mature neurons, and no longer innervate their designated targets due to the absence of this bipolar morphology. Moreover, overexpression of Annexin A6 causes some placode cell-derived neurons to form extra protrusions alongside these bipolar processes. These data demonstrate that the molecular program associated with neuronal maturation is distinct from that orchestrating changes in neuronal morphology, and, importantly, reveal Annexin A6 to be a key membrane scaffolding protein during sensory neuron membrane biogenesis. Collectively, our results provide novel insight into mechanisms underscoring morphological changes within placode cell-derived neurons that are essential for cranial gangliogenesis.
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Affiliation(s)
- Ankita Shah
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Andrew T Schiffmacher
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA
| | - Lisa A Taneyhill
- Department of Animal and Avian Sciences, University of Maryland, College Park, MD 20742, USA.
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12
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Abstract
INTRODUCTION Parkinson's disease (PD) is an insidious disorder affecting more than 1-2% of the population over the age of 65. Understanding the etiology of PD may create opportunities for developing new treatments. Genomic and transcriptomic studies are useful, but do not provide evidence for the actual status of the disease. Conversely, proteomic studies deal with proteins, which are real time players, and can hence provide information on the dynamic nature of the affected cells. The number of publications relating to the proteomics of PD is vast. Therefore, there is a need to evaluate the current proteomics literature and establish the connections between the past and the present to foresee the future. Areas covered: PubMed and Web of Science were used to retrieve the literature associated with PD proteomics. Studies using human samples, model organisms and cell lines were selected and reviewed to highlight their contributions to PD. Expert commentary: The proteomic studies associated with PD achieved only limited success in facilitating disease diagnosis, monitoring and progression. A global system biology approach using new models is needed. Future research should integrate the findings of proteomics with other omics data to facilitate both early diagnosis and the treatment of PD.
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Affiliation(s)
- Murat Kasap
- a Department of Medical Biology/DEKART Proteomics Laboratory , Kocaeli University Medical School , Kocaeli , Turkey
| | - Gurler Akpinar
- a Department of Medical Biology/DEKART Proteomics Laboratory , Kocaeli University Medical School , Kocaeli , Turkey
| | - Aylin Kanli
- a Department of Medical Biology/DEKART Proteomics Laboratory , Kocaeli University Medical School , Kocaeli , Turkey
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Dutta D, Ali N, Banerjee E, Singh R, Naskar A, Paidi RK, Mohanakumar KP. Low Levels of Prohibitin in Substantia Nigra Makes Dopaminergic Neurons Vulnerable in Parkinson's Disease. Mol Neurobiol 2017; 55:804-821. [PMID: 28062948 DOI: 10.1007/s12035-016-0328-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Accepted: 11/29/2016] [Indexed: 12/18/2022]
Abstract
Since substantia nigra (SN) and ventral tegmental area (VTA) dopaminergic neurons are, respectively, susceptible or largely unaffected in Parkinson's disease (PD), we searched for protein(s) that regulates this differential sensitivity. Differentially, expressed proteins in SN and VTA were investigated employing two-directional gel electrophoresis- matrix-assisted laser desorption ionization time of flight (MALDI-TOF-TOF) analyses. Prohibitin, which is involved in mitochondrial integrity, was validated using immunoblot, qRT-PCR, and immunohistochemistry in normal mice as well as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-model, PD postmortem human brains, and PD cybrids. In prohibitin over-expression, differentiated SH-SY5Y neurons were investigated for their susceptibility to PD neurotoxin, 1-methyl-4-phenyl-pyridnium (MPP+). Prohibitin, Hsc73, and Cu-Zn superoxide dismutase (Cu-Zn SOD) were highly expressed in VTA, whereas heat shock protein A8 (HSPA8) and 14-3-3ζ/δ were 2-fold more in SN. Prohibitin level was transiently increased in SN but unaltered in VTA on the third day of MPTP-induced mice, whereas in PD human brains, prohibitin was depleted in both these regions. Parallel to mouse SN, an enhanced prohibitin expression was found in human PD cybrids. In MPP+-induced cellular model of PD, reduction in prohibitin level was found to be associated with a loss in its binding with Ndufs3, a mitochondrial complex I protein partner. Prohibitin over-expression resisted MPP+-induced neuronal death by restoring mitochondrial membrane potential, preventing reactive oxygen species generation and cytochrome c release into cytosol. These protective phenomena exerted by prohibitin over-expression altogether hinder caspase 3 activation induced by MPP+. These results imply that prohibitin is an important negotiator protein that regulates dopaminergic cell death in SN and their protection in VTA in PD.
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Affiliation(s)
- Debashis Dutta
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Nilufar Ali
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Emili Banerjee
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Raghavendra Singh
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Amit Naskar
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Ramesh Kumar Paidi
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India
| | - Kochupurackal P Mohanakumar
- Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology, 4-Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India. .,Inter University Centre for Biomedical Research and Super Speciality Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board P.O, Kottayam, Kerala, 686009, India.
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14
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Kuter K, Kratochwil M, Marx SH, Hartwig S, Lehr S, Sugawa MD, Dencher NA. Native DIGE proteomic analysis of mitochondria from substantia nigra and striatum during neuronal degeneration and its compensation in an animal model of early Parkinson's disease. Arch Physiol Biochem 2016; 122:238-256. [PMID: 27467289 DOI: 10.1080/13813455.2016.1197948] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Cause of Parkinson's disease (PD) is still not understood. Motor symptoms are not observed at early stages of disease due to compensatory processes. Dysfunction of mitochondria was indicated already at preclinical PD. Selective toxin 6-OHDA was applied to kill dopaminergic neurons in substantia nigra and disturb neuronal transmission in striatum. Early phase of active degeneration and later stage, when surviving cells adapted to function normally, were analysed. 2D BN/SDS difference gel electrophoresis (DIGE) of mitochondrial proteome enabled to point out crucial processes involved at both time-points in dopaminergic structures. Marker proteins such as DPYSL2, HSP60, ATP1A3, EAAT2 indicated structural remodelling, cytoskeleton rearrangement, organelle trafficking, axon outgrowth and regeneration. Adaptations in dopaminergic and glutamatergic neurotransmission, recycling of synaptic vesicles, along with enlargement of mitochondria mass were proposed as causative for compensation. Changed expression of carbohydrates metabolism and oxidative phosphorylation proteins were described, including their protein-protein interactions and supercomplex assembly.
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Affiliation(s)
- Katarzyna Kuter
- a Department of Neuropsychopharmacology , Polish Academy of Sciences , Kraków , Poland
- b Physical Biochemistry, Department of Chemistry, Technische Universität Darmstadt , Darmstadt , Germany
| | - Manuela Kratochwil
- b Physical Biochemistry, Department of Chemistry, Technische Universität Darmstadt , Darmstadt , Germany
| | - Sven-Hendric Marx
- b Physical Biochemistry, Department of Chemistry, Technische Universität Darmstadt , Darmstadt , Germany
| | - Sonja Hartwig
- c Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Düsseldorf, Leibniz Center for Diabetes Research , Düsseldorf , Germany
- d German Center for Diabetes Research (DZD) , München, Neuherberg , Germany , and
| | - Stephan Lehr
- c Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at the Heinrich-Heine-University Düsseldorf, Leibniz Center for Diabetes Research , Düsseldorf , Germany
- d German Center for Diabetes Research (DZD) , München, Neuherberg , Germany , and
| | - Michiru D Sugawa
- b Physical Biochemistry, Department of Chemistry, Technische Universität Darmstadt , Darmstadt , Germany
- e Clinical Neurobiology, Charité-Universitätsmedizin , Berlin , Germany
| | - Norbert A Dencher
- b Physical Biochemistry, Department of Chemistry, Technische Universität Darmstadt , Darmstadt , Germany
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15
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Williams MJ, Perland E, Eriksson MM, Carlsson J, Erlandsson D, Laan L, Mahebali T, Potter E, Frediksson R, Benedict C, Schiöth HB. Recurrent Sleep Fragmentation Induces Insulin and Neuroprotective Mechanisms in Middle-Aged Flies. Front Aging Neurosci 2016; 8:180. [PMID: 27531979 PMCID: PMC4969361 DOI: 10.3389/fnagi.2016.00180] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 07/13/2016] [Indexed: 11/24/2022] Open
Abstract
Lack of quality sleep increases central nervous system oxidative stress and impairs removal of neurotoxic soluble metabolites from brain parenchyma. During aging poor sleep quality, caused by sleep fragmentation, increases central nervous system cellular stress. Currently, it is not known how organisms offset age-related cytotoxic metabolite increases in order to safeguard neuronal survival. Furthermore, it is not understood how age and sleep fragmentation interact to affect oxidative stress protection pathways. We demonstrate sleep fragmentation increases systems that protect against oxidative damage and neuroprotective endoplasmic reticulum molecular chaperones, as well as neuronal insulin and dopaminergic expression in middle-aged Drosophila males. Interestingly, even after sleep recovery the expression of these genes was still upregulated in middle-aged flies. Finally, sleep fragmentation generates higher levels of reactive oxygen species (ROS) in middle-aged flies and after sleep recovery these levels remain significantly higher than in young flies. The fact that neuroprotective pathways remain upregulated in middle-aged flies beyond sleep fragmentation suggests it might represent a strong stressor for the brain during later life.
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Affiliation(s)
- Michael J Williams
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Emelie Perland
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Mikaela M Eriksson
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Josef Carlsson
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Daniel Erlandsson
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Loora Laan
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Tabusi Mahebali
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Ella Potter
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Robert Frediksson
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Christian Benedict
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
| | - Helgi B Schiöth
- Functional Pharmacology, Department of Neuroscience, Uppsala University Uppsala, Sweden
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Williams MJ, Klockars A, Eriksson A, Voisin S, Dnyansagar R, Wiemerslage L, Kasagiannis A, Akram M, Kheder S, Ambrosi V, Hallqvist E, Fredriksson R, Schiöth HB. The Drosophila ETV5 Homologue Ets96B: Molecular Link between Obesity and Bipolar Disorder. PLoS Genet 2016; 12:e1006104. [PMID: 27280443 PMCID: PMC4900636 DOI: 10.1371/journal.pgen.1006104] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Accepted: 05/13/2016] [Indexed: 12/24/2022] Open
Abstract
Several reports suggest obesity and bipolar disorder (BD) share some physiological and behavioural similarities. For instance, obese individuals are more impulsive and have heightened reward responsiveness, phenotypes associated with BD, while bipolar patients become obese at a higher rate and earlier age than people without BD; however, the molecular mechanisms of such an association remain obscure. Here we demonstrate, using whole transcriptome analysis, that Drosophila Ets96B, homologue of obesity-linked gene ETV5, regulates cellular systems associated with obesity and BD. Consistent with a role in obesity and BD, loss of nervous system Ets96B during development increases triacylglyceride concentration, while inducing a heightened startle-response, as well as increasing hyperactivity and reducing sleep. Of notable interest, mouse Etv5 and Drosophila Ets96B are expressed in dopaminergic-rich regions, and loss of Ets96B specifically in dopaminergic neurons recapitulates the metabolic and behavioural phenotypes. Moreover, our data indicate Ets96B inhibits dopaminergic-specific neuroprotective systems. Additionally, we reveal that multiple SNPs in human ETV5 link to body mass index (BMI) and BD, providing further evidence for ETV5 as an important and novel molecular intermediate between obesity and BD. We identify a novel molecular link between obesity and bipolar disorder. The Drosophila ETV5 homologue Ets96B regulates the expression of cellular systems with links to obesity and behaviour, including the expression of a conserved endoplasmic reticulum molecular chaperone complex known to be neuroprotective. Finally, a connection between the obesity-linked gene ETV5 and bipolar disorder emphasizes a functional relationship between obesity and BD at the molecular level. The World Health Organization suggests obesity is a major cause of poor health and is becoming the leading public health concern. Likewise, mood-based disorders, such as bipolar disorder, are one of the top ten causes of disability worldwide. There is evidence that obesity and bipolar disorder may be linked and that obesity may exacerbate bipolar disorder symptoms. For the first time, our work evidences a molecular-link between obesity and bipolar disorder. In humans the obesity-linked gene ETV5 was also associated with bipolar disorder. Using the model organism Drosophila melanogaster (the fruit fly) we show that the ETV5 homologue Ets96B regulates a series of genes known to be neuroprotective and inhibiting the expression of Ets96 in dopaminergic neurons induces phenotypes linked to obesity and bipolar disorder, including increased lipid storage, increased anxiety and reduced sleep. Our work will help to further the understanding of how these to disorders may interact.
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Affiliation(s)
- Michael J. Williams
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
- * E-mail:
| | - Anica Klockars
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Anders Eriksson
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Sarah Voisin
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Rohit Dnyansagar
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Lyle Wiemerslage
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Anna Kasagiannis
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Mehwish Akram
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Sania Kheder
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Valerie Ambrosi
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Emilie Hallqvist
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Robert Fredriksson
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
| | - Helgi B. Schiöth
- Functional Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden
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17
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Chaudhuri AD, Choi DC, Kabaria S, Tran A, Junn E. MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression. J Biol Chem 2016; 291:6483-93. [PMID: 26801612 DOI: 10.1074/jbc.m115.691352] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2015] [Indexed: 11/06/2022] Open
Abstract
Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of pro-apoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP(+)) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3'-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP(+). Notably, overexpression of VDAC1 without the 3'-UTR significantly abolished the protective effects of miR-7 against MPP(+)-induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.
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Affiliation(s)
- Amrita Datta Chaudhuri
- From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Doo Chul Choi
- From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Savan Kabaria
- From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Alan Tran
- From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
| | - Eunsung Junn
- From the Center for Neurodegenerative and Neuroimmunologic Diseases, Department of Neurology, Rutgers - Robert Wood Johnson Medical School, Piscataway, New Jersey 08854
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18
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Ménoret A, Crocker SJ, Rodriguez A, Rathinam VA, Clark RB, Vella AT. Transition from identity to bioactivity-guided proteomics for biomarker discovery with focus on the PF2D platform. Proteomics Clin Appl 2015. [PMID: 26201056 DOI: 10.1002/prca.201500029] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Proteomic strategies provide a valuable tool kit to identify proteins involved in diseases. With recent progress in MS technology, high throughput proteomics has accelerated protein identification for potential biomarkers. Numerous biomarker candidates have been identified in several diseases, and many are common among pathologies. An overall strategy that could complement and strengthen the search for biomarkers is combining protein identity with biological outcomes. This review describes an emerging framework of bridging bioactivity to protein identity, exploring the possibility that some biomarkers will have a mechanistic role in the disease process. A review of pulmonary, cardiovascular, and CNS biomarkers will be discussed to demonstrate the utility of combining bioactivity with identification as a means to not only find meaningful biomarkers, but also to uncover functional mediators of disease.
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Affiliation(s)
- Antoine Ménoret
- Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA
| | - Stephen J Crocker
- Department of Neuroscience, University of Connecticut Health Center, Farmington, CT, USA
| | - Annabelle Rodriguez
- Department of Cell Biology, University of Connecticut Health Center, Farmington, CT, USA
| | - Vijay A Rathinam
- Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA
| | - Robert B Clark
- Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA
| | - Anthony T Vella
- Department of Immunology, University of Connecticut Health Center, Farmington, CT, USA
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19
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Wille M, Schümann A, Wree A, Kreutzer M, Glocker MO, Mutzbauer G, Schmitt O. The Proteome Profiles of the Cerebellum of Juvenile, Adult and Aged Rats--An Ontogenetic Study. Int J Mol Sci 2015; 16:21454-85. [PMID: 26370973 PMCID: PMC4613263 DOI: 10.3390/ijms160921454] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 08/04/2015] [Accepted: 08/25/2015] [Indexed: 11/16/2022] Open
Abstract
In this study, we searched for proteins that change their expression in the cerebellum (Ce) of rats during ontogenesis. This study focuses on the question of whether specific proteins exist which are differentially expressed with regard to postnatal stages of development. A better characterization of the microenvironment and its development may result from these study findings. A differential two-dimensional polyacrylamide gel electrophoresis (2DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) analysis of the samples revealed that the number of proteins of the functional classes differed depending on the developmental stages. Especially members of the functional classes of biosynthesis, regulatory proteins, chaperones and structural proteins show the highest differential expression within the analyzed stages of development. Therefore, members of these functional protein groups seem to be involved in the development and differentiation of the Ce within the analyzed development stages. In this study, changes in the expression of proteins in the Ce at different postnatal developmental stages (postnatal days (P) 7, 90, and 637) could be observed. At the same time, an identification of proteins which are involved in cell migration and differentiation was possible. Especially proteins involved in processes of the biosynthesis and regulation, the dynamic organization of the cytoskeleton as well as chaperones showed a high amount of differentially expressed proteins between the analyzed dates.
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Affiliation(s)
- Michael Wille
- Department of Anatomy, Gertrudenstr. 9, 18055 Rostock, Germany.
| | - Antje Schümann
- Department of Anatomy, Gertrudenstr. 9, 18055 Rostock, Germany.
| | - Andreas Wree
- Department of Anatomy, Gertrudenstr. 9, 18055 Rostock, Germany.
| | - Michael Kreutzer
- Proteome Center Rostock, Schillingallee 69, 18055 Rostock, Germany.
| | | | - Grit Mutzbauer
- Department of Pathology, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
| | - Oliver Schmitt
- Department of Anatomy, Gertrudenstr. 9, 18055 Rostock, Germany.
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20
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Vicente-Rodríguez M, Herradón G, Ferrer-Alcón M, Uribarri M, Pérez-García C. Chronic Cocaine Use Causes Changes in the Striatal Proteome Depending on the Endogenous Expression of Pleiotrophin. Chem Res Toxicol 2015; 28:1443-54. [DOI: 10.1021/acs.chemrestox.5b00130] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Marta Vicente-Rodríguez
- Pharmacology Laboratory, Department of
Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
| | - Gonzalo Herradón
- Pharmacology Laboratory, Department of
Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
| | | | - María Uribarri
- BRAINco Biopharma, S.L., Bizkaia Technology Park, Vizcaya, Spain
| | - Carmen Pérez-García
- Pharmacology Laboratory, Department of
Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
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The Potential of Proteomics in Understanding Neurodegeneration. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2015; 121:25-58. [DOI: 10.1016/bs.irn.2015.05.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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22
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Avalos-Fuentes A, Albarrán-Bravo S, Loya-Lopéz S, Cortés H, Recillas-Morales S, Magaña JJ, Paz-Bermúdez F, Rangel-Barajas C, Aceves J, Erlij D, Florán B. Dopaminergic denervation switches dopamine D3 receptor signaling and disrupts its Ca(2+) dependent modulation by CaMKII and calmodulin in striatonigral projections of the rat. Neurobiol Dis 2014; 74:336-46. [PMID: 25517101 DOI: 10.1016/j.nbd.2014.12.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 12/03/2014] [Accepted: 12/05/2014] [Indexed: 11/28/2022] Open
Abstract
In striatonigral projections activation of dopamine D3 receptors (D3Rs) potentiates the stimulation of GABA release and cAMP production caused by activation of dopamine D1 receptors (D1Rs). Cytoplasmic [Ca(2+)] in the terminals controls this response by modulating CaMKII, an enzyme that depresses D3R action. To examine the effects of dopamine deprivation on D3R signaling we investigated their function in striatonigral terminals of hemiparkinsonian rats. Denervation switched the signaling cascade initiated by D3R activation. In the non-lesioned side activation of D3R potentiated the stimulatory effects of D1R activation on cAMP production and K(+)-depolarization induced [(3)H] GABA release. In contrast, in the denervated side the stimulatory effects of both D1R activation and forskolin administration were blocked by D3R activation. In non-lesioned slices, D3R responses were inhibited by the activation of CaMKII produced by K(+)-depolarization (via increased Ca(2+) entry). The CaMKII-induced inhibition was blocked by the selective inhibitor KN-62. In denervated tissues the response to D3R stimulation was not modified either by K(+) depolarization or by blocking CaMKII with KN-62. Immunoblotting studies showed that depolarization-induced CaMKII binding to the D3 receptor and CaMKII phosphorylation were suppressed in denervated tissues. We also determined calmodulin expression with PCR and immunoblot techniques. Both techniques showed that calmodulin expression was depressed in the lesioned side. In sum, our studies show that dopaminergic denervation switches the D3R signaling cascade and depresses CaMKII signaling through a process that appears to involve reduced calmodulin levels. Since calmodulin is a major cytoplasmic Ca(2+) buffer our findings suggest that abnormal Ca(2+) buffering may be an important component of the abnormalities observed during dopaminergic denervation.
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Affiliation(s)
- Arturo Avalos-Fuentes
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
| | - Sacnité Albarrán-Bravo
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
| | - Santiago Loya-Lopéz
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
| | - Hernán Cortés
- Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, Mexico City, Mexico
| | - Sergio Recillas-Morales
- Facultad de Medicina Veterinaria y Zootecnia, Universidad Autónoma del Estado de México, Mexico
| | - Jonathan J Magaña
- Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute, Mexico City, Mexico
| | - Francisco Paz-Bermúdez
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
| | | | - Jorge Aceves
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico
| | - David Erlij
- Department of Physiology, SUNY Downstate Medical Center, Brooklyn, NY 11203, USA
| | - Benjamín Florán
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Mexico.
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23
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Fernández-Irigoyen J, Zelaya MV, Tuñon T, Santamaría E. Anatomo-proteomic characterization of human basal ganglia: focus on striatum and globus pallidus. Mol Brain 2014; 7:83. [PMID: 25406675 PMCID: PMC4236423 DOI: 10.1186/s13041-014-0083-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Accepted: 11/04/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND The basal ganglia (BG) are a complex network of subcortical nuclei involved in the coordination and integration of the motor activity. Although these independent anatomical structures are functionally related, the proteome present in each isolated nucleus remains largely unexplored. In order to analyse the BG proteome in a large-scale format, we used a multi-dimensional fractionation approach which combines isolation of anatomically-defined nuclei, and protein/peptide chromatographic fractionation strategies coupled to mass spectrometry. RESULTS Using this workflow, we have obtained a proteomic expression profile across striatum and globus pallidus structures among which 1681 proteins were located in caudate nucleus (CN), 1329 in putamen, 1419 in medial globus pallidus (GPi), and 1480 in lateral globus pallidus (GPe), establishing a BG reference proteome to a depth of 2979 unique proteins. Protein interactome mapping highlighted significant clustering of common proteins in striatal and pallidal structures, contributing to oxidative phosphorylation, protein degradation and neurotrophin signalling pathways. In silico analyses emphasized specific pathways represented in striatal and pallidal structures highlighting 5-hydroxytryptamine degradation, synaptic vesicle trafficking, and dopamine, metabotropic glutamate and muscarinic acetylcholine receptor pathways. Additional bioinformatic analyses also revealed that: i) nearly 4% of identified proteins have been previously associated to neurodegenerative syndromes, ii) 11% of protein set tends to localize to synaptic terminal, and iii) 20% of identified proteins were also localized in cerebrospinal fluid (CSF). CONCLUSIONS Overall, the anatomo-proteomic profiling of BG complements the anatomical atlas of the human brain transcriptome, increasing our knowledge about the molecular basis of the BG and the etiology of the movement disorders.
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Affiliation(s)
- Joaquín Fernández-Irigoyen
- />Clinical Neuroproteomics Group, Proteomics Unit, Proteored-ISCIII, Navarrabiomed, Fundación Miguel Servet, Irunlarrea Street, 31008 Pamplona, Spain
| | - María Victoria Zelaya
- />Neurological Tissue Bank, Navarrabiomed, Fundación Miguel Servet, 31008 Pamplona, Spain
| | - Teresa Tuñon
- />Pathological Anatomy Department, Navarra Hospital Complex, Pamplona, Spain
| | - Enrique Santamaría
- />Clinical Neuroproteomics Group, Proteomics Unit, Proteored-ISCIII, Navarrabiomed, Fundación Miguel Servet, Irunlarrea Street, 31008 Pamplona, Spain
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Xiong Y, Zhang Y, Iqbal J, Ke M, Wang Y, Li Y, Qing H, Deng Y. Differential expression of synaptic proteins in unilateral 6-OHDA lesioned rat model-A comparative proteomics approach. Proteomics 2014; 14:1808-19. [PMID: 24841483 DOI: 10.1002/pmic.201400069] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 04/24/2014] [Accepted: 05/15/2014] [Indexed: 12/12/2022]
Abstract
Parkinson's disease (PD) is characterized as a movement disorder due to lesions in the basal ganglia. As the major input region of the basal ganglia, striatum plays a vital role in coordinating movements. It receives afferents from the cerebral cortex and projects afferents to the internal segment of the globus pallidus and substantia nigra pars reticulate. Additionally, accumulating evidences support a role for synaptic dysfunction in PD. Therefore, the present study explores the changes in protein abundance involved in synaptic disorders in unilateral lesioned 6-OHDA rat model. Based on (18) O/(16) O-labeling technique, striatal proteins were separated using online 2D-LC, and identified by nano-ESI-quadrupole-TOF. A total of 370 proteins were identified, including 76 significantly differentially expressed proteins. Twenty-two downregulated proteins were found in composition of vesicle, ten of which were involved in neuronal transmission and recycling across synapses. These include N-ethylmaleimide-sensitive fusion protein attachment receptor proteins (SNAP-25, syntaxin-1A, syntaxin-1B, VAMP2), synapsin-1, septin-5, clathrin heavy chain 1, AP-2 complex subunit beta, dynamin-1, and endophilin-A1. Moreover, MS result for syntaxin-1A was confirmed by Western blot analysis. Overall, these synaptic changes induced by neurotoxin may serve as a reference for understanding the functional mechanism of striatum in PD.
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Affiliation(s)
- Yan Xiong
- School of Life Science, Beijing Institute of Technology, Beijing, P. R. China
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Agrawal S, Singh A, Tripathi P, Mishra M, Singh PK, Singh MP. Cypermethrin-Induced Nigrostriatal Dopaminergic Neurodegeneration Alters the Mitochondrial Function:A Proteomics Study. Mol Neurobiol 2014; 51:448-65. [DOI: 10.1007/s12035-014-8696-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Accepted: 03/24/2014] [Indexed: 12/29/2022]
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Herradón G, Pérez-García C. Targeting midkine and pleiotrophin signalling pathways in addiction and neurodegenerative disorders: recent progress and perspectives. Br J Pharmacol 2014; 171:837-48. [PMID: 23889475 PMCID: PMC3925022 DOI: 10.1111/bph.12312] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2013] [Revised: 07/09/2013] [Accepted: 07/21/2013] [Indexed: 01/03/2023] Open
Abstract
UNLABELLED Midkine (MK) and pleiotrophin (PTN) are two neurotrophic factors that are highly up-regulated in different brain regions after the administration of various drugs of abuse and in degenerative areas of the brain. A deficiency in both MK and PTN has been suggested to be an important genetic factor, which confers vulnerability to the development of the neurodegenerative disorders associated with drugs of abuse in humans. In this review, evidence demonstrating that MK and PTN limit the rewarding effects of drugs of abuse and, potentially, prevent drug relapse is compiled. There is also convincing evidence that MK and PTN have neuroprotective effects against the neurotoxicity and development of neurodegenerative disorders induced by drugs of abuse. Exogenous administration of MK and/or PTN into the CNS by means of non-invasive methods is proposed as a novel therapeutic strategy for addictive and neurodegenerative diseases. Identification of new molecular targets downstream of the MK and PTN signalling pathways or pharmacological modulation of those already known may also provide a more traditional, but probably effective, therapeutic strategy for treating addictive and neurodegenerative disorders. LINKED ARTICLES This article is part of a themed section on Midkine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-4.
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Affiliation(s)
- G Herradón
- Pharmacology lab Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San PabloBoadilla del Monte, Madrid, Spain
| | - C Pérez-García
- Pharmacology lab Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San PabloBoadilla del Monte, Madrid, Spain
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The proteome of the differentiating mesencephalic progenitor cell line CSM14.1 in vitro. BIOMED RESEARCH INTERNATIONAL 2014; 2014:351821. [PMID: 24592386 PMCID: PMC3925624 DOI: 10.1155/2014/351821] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 12/16/2013] [Indexed: 11/23/2022]
Abstract
The treatment of Parkinson's disease by transplantation of dopaminergic (DA) neurons from human embryonic mesencephalic tissue is a promising approach. However, the origin of these cells causes major problems: availability and standardization of the graft. Therefore, the generation of unlimited numbers of DA neurons from various types of stem or progenitor cells has been brought into focus. A source for DA neurons might be conditionally immortalized progenitor cells. The temperature-sensitive immortalized cell line CSM14.1 derived from the mesencephalon of an embryonic rat has been used successfully for transplantation experiments. This cell line was analyzed by unbiased stereology of cell type specific marker proteins and 2D-gel electrophoresis followed by mass spectrometry to characterize the differentially expressed proteome. Undifferentiated CSM14.1 cells only expressed the stem cell marker nestin, whereas differentiated cells expressed GFAP or NeuN and tyrosine hydroxylase. An increase of the latter cells during differentiation could be shown. By using proteomics an explanation on the protein level was found for the observed changes in cell morphology during differentiation, when CSM14.1 cells possessed the morphology of multipolar neurons. The results obtained in this study confirm the suitability of CSM14.1 cells as an in vitro model for the study of neuronal and dopaminergic differentiation in rats.
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28
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Samara A, Tsangaris GT. Brain asymmetry: both sides of the story. Expert Rev Proteomics 2014; 8:693-703. [DOI: 10.1586/epr.11.62] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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29
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Vicente-Rodríguez M, Gramage E, Herradón G, Pérez-García C. Phosphoproteomic analysis of the striatum from pleiotrophin knockout and midkine knockout mice treated with cocaine reveals regulation of oxidative stress-related proteins potentially underlying cocaine-induced neurotoxicity and neurodegeneration. Toxicology 2013; 314:166-73. [PMID: 24096156 DOI: 10.1016/j.tox.2013.09.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2013] [Revised: 09/10/2013] [Accepted: 09/25/2013] [Indexed: 12/21/2022]
Abstract
The neurotrophic factors pleiotrophin (PTN) and midkine (MK) are highly upregulated in different brain areas relevant to drug addiction after administrations of different drugs of abuse, including psychostimulants. We have previously demonstrated that PTN and MK modulate amphetamine-induced neurotoxicity and that PTN prevents cocaine-induced cytotoxicity in NG108-15 and PC12 cells. In an effort to dissect the different mechanisms of action triggered by PTN and MK to exert their protective roles against psychostimulant neurotoxicity, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN knockout, MK knockout and wild type mice treated with a single dose of cocaine (15mg/kg, i.p.). We identified 7 differentially expressed phosphoproteins: 5'(3')-deoxyribonucleotidase, endoplasmic reticulum resident protein 60 (ERP60), peroxiredoxin-6 (PRDX6), glutamate dehydrogenase 1 (GLUD1), aconitase and two subunits of hemoglobin. Most of these proteins are related to neurodegeneration processes and oxidative stress and their variations specially affect the PTN knockout mice, suggesting a protective role of endogenous PTN against cocaine-induced neural alterations. Further studies are needed to validate these proteins as possible targets against neural alterations induced by cocaine.
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Affiliation(s)
- Marta Vicente-Rodríguez
- Pharmacology Lab, Department of Pharmaceutical and Health Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
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Craft GE, Chen A, Nairn AC. Recent advances in quantitative neuroproteomics. Methods 2013; 61:186-218. [PMID: 23623823 PMCID: PMC3891841 DOI: 10.1016/j.ymeth.2013.04.008] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Revised: 03/29/2013] [Accepted: 04/13/2013] [Indexed: 01/07/2023] Open
Abstract
The field of proteomics is undergoing rapid development in a number of different areas including improvements in mass spectrometric platforms, peptide identification algorithms and bioinformatics. In particular, new and/or improved approaches have established robust methods that not only allow for in-depth and accurate peptide and protein identification and modification, but also allow for sensitive measurement of relative or absolute quantitation. These methods are beginning to be applied to the area of neuroproteomics, but the central nervous system poses many specific challenges in terms of quantitative proteomics, given the large number of different neuronal cell types that are intermixed and that exhibit distinct patterns of gene and protein expression. This review highlights the recent advances that have been made in quantitative neuroproteomics, with a focus on work published over the last five years that applies emerging methods to normal brain function as well as to various neuropsychiatric disorders including schizophrenia and drug addiction as well as of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. While older methods such as two-dimensional polyacrylamide electrophoresis continued to be used, a variety of more in-depth MS-based approaches including both label (ICAT, iTRAQ, TMT, SILAC, SILAM), label-free (label-free, MRM, SWATH) and absolute quantification methods, are rapidly being applied to neurobiological investigations of normal and diseased brain tissue as well as of cerebrospinal fluid (CSF). While the biological implications of many of these studies remain to be clearly established, that there is a clear need for standardization of experimental design and data analysis, and that the analysis of protein changes in specific neuronal cell types in the central nervous system remains a serious challenge, it appears that the quality and depth of the more recent quantitative proteomics studies is beginning to shed light on a number of aspects of neuroscience that relates to normal brain function as well as of the changes in protein expression and regulation that occurs in neuropsychiatric and neurodegenerative disorders.
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Affiliation(s)
- George E Craft
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06508
| | - Anshu Chen
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06508
| | - Angus C Nairn
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, 06508
- Yale/NIDA Neuroproteomics Center, Yale University School of Medicine, New Haven, CT, 06508
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Dixit A, Srivastava G, Verma D, Mishra M, Singh PK, Prakash O, Singh MP. Minocycline, levodopa and MnTMPyP induced changes in the mitochondrial proteome profile of MPTP and maneb and paraquat mice models of Parkinson's disease. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1227-40. [PMID: 23562983 DOI: 10.1016/j.bbadis.2013.03.019] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2012] [Revised: 03/25/2013] [Accepted: 03/26/2013] [Indexed: 12/31/2022]
Abstract
Mitochondrial dysfunction is the foremost perpetrator of the nigrostriatal dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, the roles played by majority of the mitochondrial proteins in PD pathogenesis have not yet been deciphered. The present study investigated the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and combined maneb and paraquat on the mitochondrial proteome of the nigrostriatal tissues in the presence or absence of minocycline, levodopa and manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin (MnTMPyP). The differentially expressed proteins were identified and proteome profiles were correlated with the pathological and biochemical anomalies induced by MPTP and maneb and paraquat. MPTP altered the expression of twelve while combined maneb and paraquat altered the expression of fourteen proteins. Minocycline, levodopa and MnTMPyP, respectively, restored the expression of three, seven and eight proteins in MPTP and seven, eight and eight proteins in maneb- and paraquat-treated groups. Although levodopa and MnTMPyP rescued from MPTP- and maneb- and paraquat-mediated increase in the microglial activation and decrease in manganese-superoxide dismutase expression and complex I activity, dopamine content and number of dopaminergic neurons, minocycline defended mainly against maneb- and paraquat-mediated alterations. The results demonstrate that MPTP and combined maneb and paraquat induce mitochondrial dysfunction and microglial activation and alter the expression of a bunch of mitochondrial proteins leading to the nigrostriatal dopaminergic neurodegeneration and minocycline, levodopa or MnTMPyP variably offset scores of such changes.
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Affiliation(s)
- Anubhuti Dixit
- CSIR-Indian Institute of Toxicology Research CSIR-IITR, M. G. Marg, Post Box-80, Lucknow-226 001, UP, India
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32
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Gramage E, Herradón G, Martín YB, Vicente-Rodríguez M, Rojo L, Gnekow H, Barbero A, Pérez-García C. Differential phosphoproteome of the striatum from pleiotrophin knockout and midkine knockout mice treated with amphetamine: correlations with amphetamine-induced neurotoxicity. Toxicology 2013; 306:147-56. [PMID: 23459167 DOI: 10.1016/j.tox.2013.02.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2012] [Revised: 01/30/2013] [Accepted: 02/15/2013] [Indexed: 01/13/2023]
Abstract
The neurotrophic factors pleiotrophin (PTN) and midkine (MK) have been shown to modulate amphetamine-induced neurotoxicity. Accordingly, PTN-/- and MK-/- mice show an increased vulnerability to amphetamine-induced neurotoxic effects. In an effort to uncover new pharmacological targets to prevent amphetamine neurotoxic effects, we have now used a proteomic approach to study protein phosphorylation, in which we combined phosphoprotein enrichment, by immobilized metal affinity chromatography (IMAC), with two-dimensional gel electrophoresis and mass spectrometry, in order to identify the phosphoproteins regulated in the striatum of PTN-/-, MK-/- and wild type (WT) mice treated with amphetamine. We identified 13 differentially expressed phosphoproteins that are judged to be relevant in the neuroprotective roles of PTN and MK against amphetamine-induced neurotoxicity. It is very interesting to note that 4 of these phosphoproteins, annexin A7 (ANXA7), COP9 signalosome subunit 5 (COPS5), aldehyde dehydrogenase family 1 member A1 (ALDH1A1) and creatine kinase U-type (CKMT1), are known to be involved in Parkinson's disease, a result of significant importance since PTN and MK have been also demonstrated to limit Parkinson's disease (PD) progress and have been suggested to be among the important genetic factors possibly preventing the development of PD in methamphetamine abusers. The data identify phosphoproteins differentially regulated by amphetamine treatment and/or the presence of endogenous PTN/MK which may be relevant mediators of PTN/MK neuroprotective effects against amphetamine-induced neurotoxicity. The data support further studies to validate the phosphoproteins here identified as possible new pharmacological targets to prevent amphetamine neurotoxic effects.
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Affiliation(s)
- Esther Gramage
- Pharmacology Lab, Department of Pharmaceutical and Food Sciences, Facultad de Farmacia, Universidad CEU San Pablo, Madrid, Spain
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Yadav S, Dixit A, Agrawal S, Singh A, Srivastava G, Singh AK, Srivastava PK, Prakash O, Singh MP. Rodent models and contemporary molecular techniques: notable feats yet incomplete explanations of Parkinson's disease pathogenesis. Mol Neurobiol 2012; 46:495-512. [PMID: 22736079 DOI: 10.1007/s12035-012-8291-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Accepted: 06/13/2012] [Indexed: 12/20/2022]
Abstract
Rodent models and molecular tools, mainly omics and RNA interference, have been rigorously used to decode the intangible etiology and pathogenesis of Parkinson's disease (PD). Although convention of contemporary molecular techniques and multiple rodent models paved imperative leads in deciphering the role of putative causative factors and sequential events leading to PD, complete and clear-cut mechanisms of pathogenesis are still hard to pin down. The current article reviews the implications and pros and cons of rodent models and molecular tools in understanding the molecular and cellular bases of PD pathogenesis based on the existing literature. Probable rationales for short of comprehensive leads and future possibilities in spite of the extensive applications of molecular tools and rodent models have also been discussed.
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Affiliation(s)
- Sharawan Yadav
- CSIR-Indian Institute of Toxicology Research, Lucknow-226 001, Uttar Pradesh, India
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Reduced calreticulin levels link endoplasmic reticulum stress and Fas-triggered cell death in motoneurons vulnerable to ALS. J Neurosci 2012; 32:4901-12. [PMID: 22492046 DOI: 10.1523/jneurosci.5431-11.2012] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Cellular responses to protein misfolding are thought to play key roles in triggering neurodegeneration. In the mutant superoxide dismutase (mSOD1) model of amyotrophic lateral sclerosis (ALS), subsets of motoneurons are selectively vulnerable to degeneration. Fast fatigable motoneurons selectively activate an endoplasmic reticulum (ER) stress response that drives their early degeneration while a subset of mSOD1 motoneurons show exacerbated sensitivity to activation of the motoneuron-specific Fas/NO pathway. However, the links between the two mechanisms and the molecular basis of their cellular specificity remained unclear. We show that Fas activation leads, specifically in mSOD1 motoneurons, to reductions in levels of calreticulin (CRT), a calcium-binding ER chaperone. Decreased expression of CRT is both necessary and sufficient to trigger SOD1(G93A) motoneuron death through the Fas/NO pathway. In SOD1(G93A) mice in vivo, reductions in CRT precede muscle denervation and are restricted to vulnerable motor pools. In vitro, both reduced CRT and Fas activation trigger an ER stress response that is restricted to, and required for death of, vulnerable SOD1(G93A) motoneurons. Our data reveal CRT as a critical link between a motoneuron-specific death pathway and the ER stress response and point to a role of CRT levels in modulating motoneuron vulnerability to ALS.
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Laurindo FRM, Pescatore LA, Fernandes DDC. Protein disulfide isomerase in redox cell signaling and homeostasis. Free Radic Biol Med 2012; 52:1954-69. [PMID: 22401853 DOI: 10.1016/j.freeradbiomed.2012.02.037] [Citation(s) in RCA: 183] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Revised: 02/23/2012] [Accepted: 02/24/2012] [Indexed: 12/16/2022]
Abstract
Thiol proteins may potentially act as redox signaling adaptor proteins, adjusting reactive oxygen species intermediates to specific signals and redox signals to cell homeostasis. In this review, we discuss redox effects of protein disulfide isomerase (PDI), a thioredoxin superfamily oxidoreductase from the endoplasmic reticulum (ER). Abundantly expressed PDI displays ubiquity, interactions with redox and nonredox proteins, versatile effects, and several posttranslational modifications. The PDI family contains >20 members with at least some apparent complementary actions. PDI has oxidoreductase, isomerase, and chaperone effects, the last not directly dependent on its thiols. PDI is a converging hub for pathways of disulfide bond introduction into ER-processed proteins, via hydrogen peroxide-generating mechanisms involving the oxidase Ero1α, as well as hydrogen peroxide-consuming reactions involving peroxiredoxin IV and the novel peroxidases Gpx7/8. PDI is a candidate pathway for coupling ER stress to oxidant generation. Emerging information suggests a convergence between PDI and Nox family NADPH oxidases. PDI silencing prevents Nox responses to angiotensin II and inhibits Akt phosphorylation in vascular cells and parasite phagocytosis in macrophages. PDI overexpression spontaneously enhances Nox activation and expression. In neutrophils, PDI redox-dependently associates with p47phox and supports the respiratory burst. At the cell surface, PDI exerts transnitrosation, thiol reductase, and apparent isomerase activities toward targets including adhesion and matrix proteins and proteases. Such effects mediate redox-dependent adhesion, coagulation/thrombosis, immune functions, and virus internalization. The route of PDI externalization remains elusive. Such multiple redox effects of PDI may contribute to its conspicuous expression and functional role in disease, rendering PDI family members putative redox cell signaling adaptors.
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Affiliation(s)
- Francisco R M Laurindo
- Vascular Biology Laboratory, Heart Institute (InCor), University of São Paulo School of Medicine, 05403-000 São Paulo, Brazil.
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Matusch A, Fenn LS, Depboylu C, Klietz M, Strohmer S, McLean JA, Becker JS. Combined elemental and biomolecular mass spectrometry imaging for probing the inventory of tissue at a micrometer scale. Anal Chem 2012; 84:3170-8. [PMID: 22413784 DOI: 10.1021/ac203112c] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Several complementary mass spectrometric imaging techniques allow mapping of various analytes within biological tissue sections. Laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS) quantitatively detects elements and isotopes with very high sensitivity and a particularly high dynamical range. Matrix-assisted laser desorption/ionization ion mobility mass spectrometry (MALDI-IM-MS) allows a pixel-by-pixel classification and identification of biomolecules. In order to dispose of the healthy hemisphere as an internal calibrant in addition to routinely used external standards, adjacent brain sections of mice with a unilateral 6-OHDA lesion of the medial forebrain bundle were chosen as exemplary samples. We demonstrate a comprehensive way of data acquisition and analysis by coregistering mass spectrometric data on photomicrographs as common reference space and thus providing trimodal spatial information. Registering subsequent planar element maps yielded continuous 3-dimensional data sets. Furthermore, we introduce a correction of MSI data for variable slice thickness applicable to all MSI techniques. In the present case, we observed increased concentrations of iron, manganese, and copper in the lesioned substantia nigra while monounsaturated lipid levels were decreased in the identical region of interest. Our techniques provide new insights into the intricate spatial relationship of morphology and chemistry within tissue.
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Affiliation(s)
- Andreas Matusch
- Department of Neurology, Philipps University, Marburg, Germany
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Proteomics in Parkinson's disease: An unbiased approach towards peripheral biomarkers and new therapies. J Biotechnol 2011; 156:325-37. [DOI: 10.1016/j.jbiotec.2011.08.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2011] [Revised: 06/24/2011] [Accepted: 08/08/2011] [Indexed: 12/27/2022]
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Singh BK, Kumar A, Ahmad I, Kumar V, Patel DK, Jain SK, Singh C. Oxidative stress in zinc-induced dopaminergic neurodegeneration: Implications of superoxide dismutase and heme oxygenase-1. Free Radic Res 2011; 45:1207-22. [DOI: 10.3109/10715762.2011.607164] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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