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1
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Gu J, He Y, He C, Zhang Q, Huang Q, Bai S, Wang R, You Q, Wang L. Advances in the structures, mechanisms and targeting of molecular chaperones. Signal Transduct Target Ther 2025; 10:84. [PMID: 40069202 PMCID: PMC11897415 DOI: 10.1038/s41392-025-02166-2] [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: 07/29/2024] [Revised: 11/25/2024] [Accepted: 01/15/2025] [Indexed: 03/15/2025] Open
Abstract
Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention of protein misfolding and abnormal aggregation, the modulation of protein homeostasis, and the protection of cells from damage under constantly changing environmental conditions. As the understanding of the biological mechanisms of molecular chaperones has increased, their link with the occurrence and progression of disease has suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances in determining the structures of molecular chaperones and heat shock protein 90 (HSP90) chaperone system complexes. We also describe the features of molecular chaperones and shed light on the complicated regulatory mechanism that operates through interactions with various co-chaperones in molecular chaperone cycles. In addition, how molecular chaperones affect diseases by regulating pathogenic proteins has been thoroughly analyzed. Furthermore, we focus on molecular chaperones to systematically discuss recent clinical advances and various drug design strategies in the preclinical stage. Recent studies have identified a variety of novel regulatory strategies targeting molecular chaperone systems with compounds that act through different mechanisms from those of traditional inhibitors. Therefore, as more novel design strategies are developed, targeting molecular chaperones will significantly contribute to the discovery of new potential drugs.
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Affiliation(s)
- Jinying Gu
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yanyi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Chenxi He
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qiuyue Zhang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Qifei Huang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shangjun Bai
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ruoning Wang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China.
- Jiangsu Provincial TCM Engineering Technology Research Center of Highly Efficient Drug Delivery Systems (DDSs), Nanjing, China.
| | - Qidong You
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Lei Wang
- State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China.
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
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Sedlacek J, Smahelova Z, Adamek M, Subova D, Svobodova L, Kadlecova A, Majer P, Machara A, Grantz Saskova K. Small-molecule activators of NRF1 transcriptional activity prevent protein aggregation. Biomed Pharmacother 2025; 183:117864. [PMID: 39884031 DOI: 10.1016/j.biopha.2025.117864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/01/2025] Open
Abstract
Intracellular protein aggregation causes proteotoxic stress, underlying highly debilitating neurodegenerative disorders in parallel with decreased proteasome activity. Nevertheless, under such stress conditions, the expression of proteasome subunits is upregulated by Nuclear Factor Erythroid 2-related factor 1 (NRF1), a transcription factor that is encoded by NFE2L1. Activating the NRF1 pathway could accordingly delay the onset of neurodegenerative and other disorders with impaired cell proteostasis. Here, we present a series of small-molecule compounds based on bis(phenylmethylen)cycloalkanones and their heterocyclic analogues, identified via targeted library screening, that can induce NRF1-dependent downstream events, such as proteasome synthesis, heat shock response, and autophagy, in both model cell lines and Caenorhabditis elegans strains. These compounds increase proteasome activity and decrease the size and number of protein aggregates without causing any cellular stress or inhibiting the ubiquitin-proteasome system (UPS). Therefore, our compounds represent a new promising therapeutic approach for various protein conformational diseases, including the most debilitating neurodegenerative diseases.
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Affiliation(s)
- Jindrich Sedlacek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
| | - Zuzana Smahelova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
| | - Michael Adamek
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic
| | - Dominika Subova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic; First Faculty of Medicine & General University Hospital, Charles University, U Nemocnice 2, Prague 2 12808, Czech Republic
| | - Lucie Svobodova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Organic Chemistry, Charles University, Hlavova 2030/8, Prague 2 12843, Czech Republic
| | - Alena Kadlecova
- Department of Experimental Biology, Palacky University, Slechtitelu 27, Olomouc 78371, Czech Republic
| | - Pavel Majer
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic
| | - Ales Machara
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic.
| | - Klara Grantz Saskova
- Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Flemingovo n. 2, Prague 16610, Czech Republic; Department of Genetics and Microbiology, Charles University and Research Center BIOCEV, Prumyslova 595, Vestec 25250, Czech Republic.
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Chakraborty P, Zweckstetter M. Interplay of p23 with FKBP51 and their chaperone complex in regulating tau aggregation. Nat Commun 2025; 16:669. [PMID: 39809798 PMCID: PMC11733250 DOI: 10.1038/s41467-025-56028-0] [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: 12/27/2023] [Accepted: 01/06/2025] [Indexed: 01/30/2025] Open
Abstract
The pathological deposition of tau and amyloid-beta into insoluble amyloid fibrils are pathological hallmarks of Alzheimer's disease. Molecular chaperones are important cellular factors contributing to the regulation of tau misfolding and aggregation. Here we reveal an Hsp90-independent mechanism by which the co-chaperone p23 as well as a molecular complex formed by two co-chaperones, p23 and FKBP51, modulates tau aggregation. Integrating NMR spectroscopy, SAXS, molecular docking, and site-directed mutagenesis we reveal the structural basis of the p23-FKBP51 complex. We show that p23 specifically recognizes the TPR domain of FKBP51 and interacts with tau through its C-terminal disordered tail. We further show that the p23-FKBP51 complex binds tau to form a dynamic p23-FKBP51-tau trimeric complex that delays tau aggregation and thus may counteract Hsp90-FKBP51 mediated toxicity. Taken together, our findings reveal a co-chaperone mediated Hsp90-independent chaperoning of tau protein.
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Affiliation(s)
- Pijush Chakraborty
- Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany
| | - Markus Zweckstetter
- Department for NMR-based Structural Biology, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
- German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.
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Sangotra A, Lieberman AP. Therapeutic targeting of the polyglutamine androgen receptor in Spinal and Bulbar Muscular Atrophy. Expert Opin Ther Targets 2025; 29:29-41. [PMID: 39915972 PMCID: PMC11888889 DOI: 10.1080/14728222.2025.2464173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 02/03/2025] [Indexed: 02/12/2025]
Abstract
INTRODUCTION Spinal and Bulbar Muscular Atrophy (SBMA) is a slowly progressive, X-linked, and sex-limited degenerative disorder affecting lower motor neurons and skeletal muscle which lacks disease-modifying therapies. This disease is caused by a CAG/polyglutamine (polyQ) tract expansion in the androgen receptor (AR) gene, and its pathogenesis is driven by toxic gain-of-function mechanisms. Affected men develop proximal limb and bulbar muscle weakness along with signs of partial androgen insensitivity. AREAS COVERED Toxicity of the polyQ AR is mediated by protein misfolding and nuclear translocation that follow ligand binding, resulting in the disruption of downstream homeostatic mechanisms. This review highlights what is known about disease pathogenesis and how this has been leveraged to test potential therapeutic approaches. The focus is on strategies that alleviate polyQ AR toxicity in SBMA, including those that alter AR function, diminish the expression of the encoding gene, or promote clearance of the misfolded, mutant protein. EXPERT OPINION We discuss emerging strategies to mitigate polyQ AR toxicity, including gene editing, RNA targeted therapies, and efforts to harness proteostatic mechanisms. These promising approaches are discussed in the context of challenges for drug discovery efforts that are faced when attempting to treat a rare and slowly progressive neurodegenerative disorder.
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MESH Headings
- Humans
- Receptors, Androgen/metabolism
- Animals
- Peptides/pharmacology
- Male
- Molecular Targeted Therapy
- Bulbo-Spinal Atrophy, X-Linked/physiopathology
- Bulbo-Spinal Atrophy, X-Linked/drug therapy
- Bulbo-Spinal Atrophy, X-Linked/therapy
- Bulbo-Spinal Atrophy, X-Linked/genetics
- Protein Folding
- Gene Editing
- Muscular Atrophy, Spinal/drug therapy
- Muscular Atrophy, Spinal/physiopathology
- Muscular Atrophy, Spinal/genetics
- Muscular Atrophy, Spinal/therapy
- Muscular Atrophy, Spinal/metabolism
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Affiliation(s)
- Agamjot Sangotra
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Andrew P. Lieberman
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
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Kitson RRA, Kitsonová D, Siegel D, Ross D, Moody CJ. Geldanamycin, a Naturally Occurring Inhibitor of Hsp90 and a Lead Compound for Medicinal Chemistry. J Med Chem 2024; 67:17946-17963. [PMID: 39361055 PMCID: PMC11513894 DOI: 10.1021/acs.jmedchem.4c01048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 09/17/2024] [Accepted: 09/20/2024] [Indexed: 10/25/2024]
Abstract
Geldanamycin remains a driver in the medicinal chemistry of heat shock protein 90 (Hsp90) inhibition, even half a century after its original isolation from nature. This Perspective focuses on the properties of the benzoquinone ring of the natural product that enable a range of functionalization reactions to take place. Therefore, inherent reactivity at C-17, where the methoxy group serves as a vinylogous ester, and at C-19 that demonstrates nucleophilic, enamide-type character toward electrophiles, and also as a conjugate acceptor to react with nucleophiles, has facilitated the synthesis of semisynthetic derivatives. Thus, a range of C-17-substituted amine derivatives has been investigated in oncology applications, with a number of compounds in this series reaching clinical trials. In contrast, the 19-position of geldanamycin has received less attention, although 19-substituted derivatives offer promise with markedly reduced toxicity compared to geldanamycin itself, while retaining Hsp90 inhibitory activity albeit with diminished potency in cellular studies.
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Affiliation(s)
- Russell R. A. Kitson
- Department
of Organic and Bioorganic Chemistry, Charles
University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203, 50005 Hradec Králové, Czech Republic
| | - Dominika Kitsonová
- Datwyler
Sealing Technologies CZ Ltd., Polní 224, 50401 Nový Bydžov, Czech
Republic
| | - David Siegel
- Department
of Pharmaceutical Sciences, University of
Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
| | - David Ross
- Department
of Pharmaceutical Sciences, University of
Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, Aurora, Colorado 80045, United States
| | - Christopher J. Moody
- School
of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, U.K.
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Hu D, Yan C, Xie H, Wen X, He K, Ding Y, Zhao Y, Meng H, Li K, Yang Z. Perihematomal Neurovascular Protection: Blocking HSP90 Reduces Blood Infiltration Associated with Inflammatory Effects Following Intracerebral Hemorrhage in Rates. Transl Stroke Res 2024:10.1007/s12975-024-01289-y. [PMID: 39230786 DOI: 10.1007/s12975-024-01289-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/30/2024] [Accepted: 08/12/2024] [Indexed: 09/05/2024]
Abstract
The active hemorrhage surrounding the hematoma is caused by the infiltration of blood into the cerebral parenchyma through the ruptured vessel, including the compromised blood-brain barrier (BBB). This process is thought to be mainly driven by inflammation and serves as a significant pathological characteristic that contributes to the neurological deterioration observed in individuals with intracerebral hemorrhage (ICH). Heat shock protein 90 (HSP90) exhibits abnormally high expression levels in various diseases and is closely associated with the onset of inflammation. Here, we found that blocking HSP90 effectively alleviates the inflammatory damage to BBB and subsequent bleeding around the hematoma. We have observed increased HSP90 levels in the serum of patients with ICH and the perihematoma region in ICH rats. Treatment with anti-HSP90 drugs (Geldanamycin and radicicol) effectively reduced HSP90 levels, resulting in enhanced neurological outcomes, decreased hematoma volume, and prevented peripheral immune cells from adhering to the BBB and infiltrating the brain parenchyma surrounding the hematoma in ICH rats. Mechanistically, anti-HSP90 therapy alleviated BBB injury caused by ICH-induced inflammation by suppressing TLR4 signaling. The study highlights the potential of anti-HSP90 therapy in mitigating BBB disruption and hemorrhage surrounding the hematoma, providing new insights into the management of ICH by targeting HSP90.
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Affiliation(s)
- Di Hu
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Chao Yan
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Hesong Xie
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Xueyi Wen
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Kejing He
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Yan Ding
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Ying Zhao
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China
| | - Heng Meng
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China.
| | - Keshen Li
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China.
| | - Zhenguo Yang
- Department of Neurology and Stroke Center, Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, 613 West Huangpu Ave, Guangzhou, 510632, China.
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7
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Zhou Y, Chen Z, Liu S, Liu S, Liao Y, Du A, Dong Z, Zhang Y, Chen X, Tao S, Wu X, Razzaq A, Xu G, Tan DA, Li S, Deng Y, Peng J, Dai S, Deng X, Zhang X, Jiang T, Zhang Z, Cheng G, Zhao J, Xia Z. A Cullin 5-based complex serves as an essential modulator of ORF9b stability in SARS-CoV-2 replication. Signal Transduct Target Ther 2024; 9:159. [PMID: 38937432 PMCID: PMC11211426 DOI: 10.1038/s41392-024-01874-5] [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: 10/29/2023] [Revised: 04/12/2024] [Accepted: 05/15/2024] [Indexed: 06/29/2024] Open
Abstract
The ORF9b protein, derived from the nucleocapsid's open-reading frame in both SARS-CoV and SARS-CoV-2, serves as an accessory protein crucial for viral immune evasion by inhibiting the innate immune response. Despite its significance, the precise regulatory mechanisms underlying its function remain elusive. In the present study, we unveil that the ORF9b protein of SARS-CoV-2, including emerging mutant strains like Delta and Omicron, can undergo ubiquitination at the K67 site and subsequent degradation via the proteasome pathway, despite certain mutations present among these strains. Moreover, our investigation further uncovers the pivotal role of the translocase of the outer mitochondrial membrane 70 (TOM70) as a substrate receptor, bridging ORF9b with heat shock protein 90 alpha (HSP90α) and Cullin 5 (CUL5) to form a complex. Within this complex, CUL5 triggers the ubiquitination and degradation of ORF9b, acting as a host antiviral factor, while HSP90α functions to stabilize it. Notably, treatment with HSP90 inhibitors such as GA or 17-AAG accelerates the degradation of ORF9b, leading to a pronounced inhibition of SARS-CoV-2 replication. Single-cell sequencing data revealed an up-regulation of HSP90α in lung epithelial cells from COVID-19 patients, suggesting a potential mechanism by which SARS-CoV-2 may exploit HSP90α to evade the host immunity. Our study identifies the CUL5-TOM70-HSP90α complex as a critical regulator of ORF9b protein stability, shedding light on the intricate host-virus immune response dynamics and offering promising avenues for drug development against SARS-CoV-2 in clinical settings.
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Affiliation(s)
- Yuzheng Zhou
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
| | - Zongpeng Chen
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Sijie Liu
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Sixu Liu
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Yujie Liao
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Ashuai Du
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Zijun Dong
- Department of Basic Medicine, School of Medicine, Hunan Normal University, 410081, Changsha, China
| | - Yongxing Zhang
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Xuan Chen
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Siyi Tao
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Xin Wu
- Department of spine surgery, The Third Xiangya Hospital, Central South University, 410013, Changsha, China
| | - Aroona Razzaq
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Gang Xu
- School of Basic Medical Sciences, Anhui Medical University, 230032, Hefei, China
| | - De-An Tan
- Hunan Key Laboratory of Neurorestoratology, 921 Hospital of Joint Logistics Support Force People's Liberation Army of China (The Second Affiliated Hospital of Hunan Normal University), 410003, Changsha, Hunan, China
| | - Shanni Li
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China
| | - Youwen Deng
- Department of spine surgery, The Third Xiangya Hospital, Central South University, 410013, Changsha, China
| | - Jian Peng
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, 410008, Changsha, China
| | - Shuyan Dai
- Xiangya School of Pharmaceutical Sciences, Central South University, 410013, Changsha, China
| | - Xu Deng
- Xiangya School of Pharmaceutical Sciences, Central South University, 410013, Changsha, China
| | - Xianwen Zhang
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, 518132, Shenzhen, China
| | | | - Zheng Zhang
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
| | - Gong Cheng
- Institute of Infectious Diseases, Shenzhen Bay Laboratory, 518132, Shenzhen, China
- Tsinghua University-Peking University Joint Center for Life Sciences, School of Medicine, Tsinghua University, 100084, Beijing, China
| | - Jincun Zhao
- Institute for Hepatology, National Clinical Research Center for Infectious Disease, Shenzhen Third People's Hospital, The Second Affiliated Hospital, School of Medicine, Southern University of Science and Technology, 518112, Shenzhen, China
- Guangzhou Laboratory, 510005, Guangzhou, China
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, 510120, Guangzhou, China
| | - Zanxian Xia
- Department of Cell Biology, School of Life Sciences, Central South University, 410013, Changsha, China.
- Hunan Key Laboratory of Animal Models for Human Diseases, Hunan Key Laboratory of Medical Genetics & Center for Medical Genetics, School of Life Sciences, Central South University, 410008, Changsha, China.
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8
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Paul JW, Muratcioğlu S, Kuriyan J. A fluorescence-based sensor for calibrated measurement of protein kinase stability in live cells. Protein Sci 2024; 33:e5023. [PMID: 38801214 PMCID: PMC11129626 DOI: 10.1002/pro.5023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/22/2024] [Accepted: 05/02/2024] [Indexed: 05/29/2024]
Abstract
Oncogenic mutations can destabilize signaling proteins, resulting in increased or unregulated activity. Thus, there is considerable interest in mapping the relationship between mutations and the stability of signaling proteins, to better understand the consequences of oncogenic mutations and potentially inform the development of new therapeutics. Here, we develop a tool to study protein-kinase stability in live mammalian cells and the effects of the HSP90 chaperone system on the stability of these kinases. We determine the expression levels of protein kinases by monitoring the fluorescence of fluorescent proteins fused to those kinases, normalized to that of co-expressed reference fluorescent proteins. We used this tool to study the dependence of Src- and Raf-family kinases on the HSP90 system. We demonstrate that this sensor reports on destabilization induced by oncogenic mutations in these kinases. We also show that Src-homology 2 and Src-homology 3 domains, which are required for autoinhibition of Src-family kinases, stabilize these kinase domains in the cell. Our expression-calibrated sensor enables the facile characterization of the effects of mutations and small-molecule drugs on protein-kinase stability.
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Affiliation(s)
- Joseph W. Paul
- Department of Molecular and Cell BiologyUniversity of CaliforniaBerkeleyCaliforniaUSA
- California Institute for Quantitative Bioscience (QB3)University of CaliforniaBerkeleyCaliforniaUSA
| | - Serena Muratcioğlu
- Department of BiochemistryVanderbilt University School of MedicineNashvilleTennesseeUSA
| | - John Kuriyan
- Department of BiochemistryVanderbilt University School of MedicineNashvilleTennesseeUSA
- Department of ChemistryVanderbilt UniversityNashvilleTennesseeUSA
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9
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Bonsor M, Ammar O, Schnoegl S, Wanker EE, Silva Ramos E. Polyglutamine disease proteins: Commonalities and differences in interaction profiles and pathological effects. Proteomics 2024; 24:e2300114. [PMID: 38615323 DOI: 10.1002/pmic.202300114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 03/25/2024] [Accepted: 03/27/2024] [Indexed: 04/16/2024]
Abstract
Currently, nine polyglutamine (polyQ) expansion diseases are known. They include spinocerebellar ataxias (SCA1, 2, 3, 6, 7, 17), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and Huntington's disease (HD). At the root of these neurodegenerative diseases are trinucleotide repeat mutations in coding regions of different genes, which lead to the production of proteins with elongated polyQ tracts. While the causative proteins differ in structure and molecular mass, the expanded polyQ domains drive pathogenesis in all these diseases. PolyQ tracts mediate the association of proteins leading to the formation of protein complexes involved in gene expression regulation, RNA processing, membrane trafficking, and signal transduction. In this review, we discuss commonalities and differences among the nine polyQ proteins focusing on their structure and function as well as the pathological features of the respective diseases. We present insights from AlphaFold-predicted structural models and discuss the biological roles of polyQ-containing proteins. Lastly, we explore reported protein-protein interaction networks to highlight shared protein interactions and their potential relevance in disease development.
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Affiliation(s)
- Megan Bonsor
- Department of Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Orchid Ammar
- Department of Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Sigrid Schnoegl
- Department of Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Erich E Wanker
- Department of Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Eduardo Silva Ramos
- Department of Neuroproteomics, Max Delbrück Center for Molecular Medicine, Berlin, Germany
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10
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Pal R, Hui D, Menchen H, Zhao H, Mozziconacci O, Wilkins H, Blagg BSJ, Schöneich C, Swerdlow RH, Michaelis ML, Michaelis EK. Protection against Aβ-induced neuronal damage by KU-32: PDHK1 inhibition as important target. Front Aging Neurosci 2023; 15:1282855. [PMID: 38035268 PMCID: PMC10682733 DOI: 10.3389/fnagi.2023.1282855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
A feature of most neurodegenerative diseases is the presence of "mis-folded proteins" that form aggregates, suggesting suboptimal activity of neuronal molecular chaperones. Heat shock protein 90 (Hsp90) is the master regulator of cell responses to "proteotoxic" stresses. Some Hsp90 modulators activate cascades leading to upregulation of additional chaperones. Novobiocin is a modulator at the C-terminal ATP-binding site of Hsp90. Of several novobiocin analogs synthesized and tested for protection against amyloid beta (Aβ)-induced neuronal death, "KU-32" was the most potent in protecting primary neurons, but did not increase expression of other chaperones believed to help clear misfolded proteins. However, KU-32 reversed Aβ-induced superoxide formation, activated Complex I of the electron transfer chain in mitochondria, and blocked the Aβ-induced inhibition of Complex I in neuroblastoma cells. A mechanism for these effects of KU-32 on mitochondrial metabolism appeared to be the inhibition of pyruvate dehydrogenase kinase (PDHK), both in isolated brain mitochondria and in SH-SY5Y cells. PDHK inhibition by the classic enzyme inhibitor, dichloroacetate, led to neuroprotection from Aβ25-35-induced cell injury similarly to KU-32. Inhibition of PDHK in neurons would lead to activation of the PDH complex, increased acetyl-CoA generation, stimulation of the tricarboxylic acid cycle and Complex I in the electron transfer chain, and enhanced oxidative phosphorylation. A focus of future studies may be on the potential value of PDHK as a target in AD therapy.
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Affiliation(s)
- Ranu Pal
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
| | - Dongwei Hui
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
| | - Heather Menchen
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
| | - Huiping Zhao
- Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, United States
| | - Olivier Mozziconacci
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Heather Wilkins
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Brian S. J. Blagg
- Department of Medicinal Chemistry, University of Kansas, Lawrence, KS, United States
- Department of Chemistry and Biochemistry, University of Notre Dame, South Bend, IN, United States
| | - Christian Schöneich
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
| | - Russell H. Swerdlow
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Mary L. Michaelis
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, United States
| | - Elias K. Michaelis
- Higuchi Biosciences Center, University of Kansas, Lawrence, KS, United States
- Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS, United States
- University of Kansas Alzheimer’s Disease Research Center, University of Kansas Medical Center, Kansas City, KS, United States
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11
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Garofalo M, Bonanno S, Marcuzzo S, Pandini C, Scarian E, Dragoni F, Di Gerlando R, Bordoni M, Parravicini S, Gellera C, Masson R, Dosi C, Zanin R, Pansarasa O, Cereda C, Berardinelli A, Gagliardi S. Preliminary insights into RNA in CSF of pediatric SMA patients after 6 months of nusinersen. Biol Direct 2023; 18:57. [PMID: 37705059 PMCID: PMC10498611 DOI: 10.1186/s13062-023-00413-6] [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: 07/13/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023] Open
Abstract
BACKGROUND Spinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (Spinraza®) modulates the pre-mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery. METHODS By RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0). RESULTS We observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into "homogeneous" and "heterogeneous" according to their gene expression pattern. The "heterogeneous" group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern. CONCLUSIONS This study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.
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Affiliation(s)
| | - S Bonanno
- Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - S Marcuzzo
- Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - C Pandini
- Department of Biosciences, University of Milan, Milan, Italy
| | - E Scarian
- IRCCS Mondino Foundation, Pavia, Italy
| | - F Dragoni
- IRCCS Mondino Foundation, Pavia, Italy
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - R Di Gerlando
- IRCCS Mondino Foundation, Pavia, Italy
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy
| | - M Bordoni
- IRCCS Mondino Foundation, Pavia, Italy
| | - S Parravicini
- IRCCS Mondino Foundation, Pavia, Italy
- Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy
| | - C Gellera
- Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - R Masson
- Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - C Dosi
- Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | - R Zanin
- Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy
| | | | - C Cereda
- Center of Functional Genomics and Rare Diseases, V. Buzzi Children's Hospital, 20154, Milan, Italy
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12
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Kim H, Gomez-Pastor R. HSF1 and Its Role in Huntington's Disease Pathology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1410:35-95. [PMID: 36396925 DOI: 10.1007/5584_2022_742] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
PURPOSE OF REVIEW Heat shock factor 1 (HSF1) is the master transcriptional regulator of the heat shock response (HSR) in mammalian cells and is a critical element in maintaining protein homeostasis. HSF1 functions at the center of many physiological processes like embryogenesis, metabolism, immune response, aging, cancer, and neurodegeneration. However, the mechanisms that allow HSF1 to control these different biological and pathophysiological processes are not fully understood. This review focuses on Huntington's disease (HD), a neurodegenerative disease characterized by severe protein aggregation of the huntingtin (HTT) protein. The aggregation of HTT, in turn, leads to a halt in the function of HSF1. Understanding the pathways that regulate HSF1 in different contexts like HD may hold the key to understanding the pathomechanisms underlying other proteinopathies. We provide the most current information on HSF1 structure, function, and regulation, emphasizing HD, and discussing its potential as a biological target for therapy. DATA SOURCES We performed PubMed search to find established and recent reports in HSF1, heat shock proteins (Hsp), HD, Hsp inhibitors, HSF1 activators, and HSF1 in aging, inflammation, cancer, brain development, mitochondria, synaptic plasticity, polyglutamine (polyQ) diseases, and HD. STUDY SELECTIONS Research and review articles that described the mechanisms of action of HSF1 were selected based on terms used in PubMed search. RESULTS HSF1 plays a crucial role in the progression of HD and other protein-misfolding related neurodegenerative diseases. Different animal models of HD, as well as postmortem brains of patients with HD, reveal a connection between the levels of HSF1 and HSF1 dysfunction to mutant HTT (mHTT)-induced toxicity and protein aggregation, dysregulation of the ubiquitin-proteasome system (UPS), oxidative stress, mitochondrial dysfunction, and disruption of the structural and functional integrity of synaptic connections, which eventually leads to neuronal loss. These features are shared with other neurodegenerative diseases (NDs). Currently, several inhibitors against negative regulators of HSF1, as well as HSF1 activators, are developed and hold promise to prevent neurodegeneration in HD and other NDs. CONCLUSION Understanding the role of HSF1 during protein aggregation and neurodegeneration in HD may help to develop therapeutic strategies that could be effective across different NDs.
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Affiliation(s)
- Hyuck Kim
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Rocio Gomez-Pastor
- Department of Neuroscience, School of Medicine, University of Minnesota, Minneapolis, MN, USA.
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13
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Prodromou C, Aran-Guiu X, Oberoi J, Perna L, Chapple JP, van der Spuy J. HSP70-HSP90 Chaperone Networking in Protein-Misfolding Disease. Subcell Biochem 2023; 101:389-425. [PMID: 36520314 DOI: 10.1007/978-3-031-14740-1_13] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
Molecular chaperones and their associated co-chaperones are essential in health and disease as they are key facilitators of protein-folding, quality control and function. In particular, the heat-shock protein (HSP) 70 and HSP90 molecular chaperone networks have been associated with neurodegenerative diseases caused by aberrant protein-folding. The pathogenesis of these disorders usually includes the formation of deposits of misfolded, aggregated protein. HSP70 and HSP90, plus their co-chaperones, have been recognised as potent modulators of misfolded protein toxicity, inclusion formation and cell survival in cellular and animal models of neurodegenerative disease. Moreover, these chaperone machines function not only in folding but also in proteasome-mediated degradation of neurodegenerative disease proteins. This chapter gives an overview of the HSP70 and HSP90 chaperones, and their respective regulatory co-chaperones, and explores how the HSP70 and HSP90 chaperone systems form a larger functional network and its relevance to counteracting neurodegenerative disease associated with misfolded proteins and disruption of proteostasis.
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Affiliation(s)
| | - Xavi Aran-Guiu
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK
| | - Jasmeen Oberoi
- Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK
| | - Laura Perna
- Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - J Paul Chapple
- Centre for Endocrinology, William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, UK.
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14
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Loss of MTCH-1 suppresses age-related proteostasis collapse through the inhibition of programmed cell death factors. Cell Rep 2022; 41:111690. [DOI: 10.1016/j.celrep.2022.111690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 09/12/2022] [Accepted: 10/28/2022] [Indexed: 11/23/2022] Open
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15
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Tassone G, Mazzorana M, Pozzi C. Structural Basis of Parasitic HSP90 ATPase Inhibition by Small Molecules. Pharmaceuticals (Basel) 2022; 15:1341. [PMID: 36355513 PMCID: PMC9692773 DOI: 10.3390/ph15111341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 09/10/2024] Open
Abstract
Protozoan parasites are responsible for several harmful and widespread human diseases that cause high morbidity and mortality. Currently available treatments have serious limitations due to poor efficiency, strong adverse effects, and high cost. Hence, the identification of new targets and the development of specific drug therapies against parasitic diseases are urgent needs. Heat shock protein 90 (HSP90) is an ATP-dependent molecular chaperone that plays a key role in parasite survival during the various differentiation stages, spread over the vector insect and the human host, which they undergo during their life cycle. The N-terminal domain (NTD) of HSP90, containing the main determinants for ATPase activity, represents the most druggable domain for inhibitor targeting. The molecules investigated on parasite HSP90 are mainly developed from known inhibitors of the human counterpart, and they have strong limitations due to selectivity issues, accounting for the high conservation of the ATP-binding site between the parasite and human proteins. The current review highlights the recent structural progress made to support the rational design of new molecules able to effectively block the chaperone activity of parasite HSP90.
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Affiliation(s)
- Giusy Tassone
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
| | - Marco Mazzorana
- Diamond Light Source Ltd., Diamond House, Harwell Science & Innovation Campus, Didcot OX11 0DE, UK
| | - Cecilia Pozzi
- Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018–2022, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
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16
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The current state of amyloidosis therapeutics and the potential role of fluorine in their treatment. Biochimie 2022; 202:123-135. [PMID: 35963462 DOI: 10.1016/j.biochi.2022.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 07/22/2022] [Accepted: 08/04/2022] [Indexed: 11/22/2022]
Abstract
Amyloidosis, commonly known as amyloid-associated diseases, is characterized by improperly folded proteins accumulating in tissues and eventually causing organ damage, which is linked to several disorders ranging from neurodegenerative to peripheral diseases. It has an enormous societal and financial impact on the global health sector. Due to the complexity of protein misfolding and intertwined aggregation, there are no effective disease-modifying medications at present, and the condition is likely mis/non-diagnosed half of the time. Nonetheless, over the last two decades, substantial research into aggregation processes has revealed the possibilities of new intervention approaches. On the other hand, fluorine has been a rising star in therapeutic development for numerous neurodegenerative illnesses and other peripheral diseases. In this study, we revised and emphasized the possible significance of fluorine-modified therapeutic molecules and fluorine-modified nanoparticles (NPs) in the modulation of amyloidogenic proteins, including insulin, amyloid beta peptide (Aβ), prion protein (PrP), transthyretin (TTR) and Huntingtin (htt).
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17
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Ko JC, Chen JC, Hsieh JM, Tseng PY, Chiang CS, Liu LL, Chien CC, Huang IH, Chang QZ, Mu BC, Lin YW. Heat shock protein 90 inhibitor 17-AAG down-regulates thymidine phosphorylase expression and potentiates the cytotoxic effect of tamoxifen and erlotinib in human lung squamous carcinoma cells. Biochem Pharmacol 2022; 204:115207. [PMID: 35961402 DOI: 10.1016/j.bcp.2022.115207] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/02/2022]
Abstract
Elevated thymidine phosphorylase (TP) levels, a key enzyme in the pyrimidine nucleoside salvage pathway, in cancer cells, are related to a poor prognosis in a variety of cancers. Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is involved in the stabilization and maturation of many oncogenic proteins. The aim of this study is to elucidate whether Hsp90 inhibitor 17-AAG could enhance tamoxifen- and erlotinib-induced cytotoxicity in nonsmall cell lung cancer (NSCLC) cells via modulating TP expression in two squamous NSCLC cell lines, H520 and H1703. We found that 17-AAG reduced TP expression via inactivating the MKK1/2-ERK1/2-mitogen-activated protein kinase (MAPK) pathway. TP knockdown with siRNA or ERK1/2 MAPK inactivation with the pharmacological inhibitor U0126 could enhance the cytotoxic and growth inhibitory effects of 17-AAG. In contrast, MKK1-CA or MKK2-CA (a constitutively active form of MKK1/2) vector-enforced expression could reduce the cytotoxic and cell growth inhibitory effects of 17-AAG. Furthermore, 17-AAG enhanced the cytotoxic and cell growth inhibitory effects of tamoxifen and erlotinib in NSCLC cells, which were associated with TP expression downregulation and MKK1/2-ERK1/2 signal inactivation. Taken together, Hsp90 inhibition downregulates TP, enhancing the tamoxifen- and erlotinib-induced cytotoxicity in H520 and H1703 cells.
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Affiliation(s)
- Jen-Chung Ko
- Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Taiwan
| | - Jyh-Cheng Chen
- Department of Food Science, National Chiayi University, Chiayi, Taiwan
| | - Jou-Min Hsieh
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Pei-Yu Tseng
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Chen-Shan Chiang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Li-Ling Liu
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Chin-Cheng Chien
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - I-Hsiang Huang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Qiao-Zhen Chang
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Bo-Cheng Mu
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan
| | - Yun-Wei Lin
- Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
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18
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Ogura Y, Sahashi K, Hirunagi T, Iida M, Miyata T, Katsuno M. Mid1 is associated with androgen-dependent axonal vulnerability of motor neurons in spinal and bulbar muscular atrophy. Cell Death Dis 2022; 13:601. [PMID: 35821212 PMCID: PMC9276699 DOI: 10.1038/s41419-022-05001-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 05/31/2022] [Accepted: 06/07/2022] [Indexed: 01/21/2023]
Abstract
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset hereditary neurodegenerative disease caused by the expansions of CAG repeats in the androgen receptor (AR) gene. Androgen-dependent nuclear accumulation of pathogenic AR protein causes degeneration of lower motor neurons, leading to progressive muscle weakness and atrophy. While the successful induction of SBMA-like pathology has been achieved in mouse models, mechanisms underlying motor neuron vulnerability remain unclear. In the present study, we performed a transcriptome-based screening for genes expressed exclusively in motor neurons and dysregulated in the spinal cord of SBMA mice. We found upregulation of Mid1 encoding a microtubule-associated RNA binding protein which facilitates the translation of CAG-expanded mRNAs. Based on the finding that lower motor neurons begin expressing Mid1 during embryonic stages, we developed an organotypic slice culture system of the spinal cord obtained from SBMA mouse fetuses to study the pathogenic role of Mid1 in SBMA motor neurons. Impairment of axonal regeneration arose in the spinal cord culture in SBMA mice in an androgen-dependent manner, but not in mice with non-CAG-expanded AR, and was either exacerbated or ameliorated by Mid1 overexpression or knockdown, respectively. Hence, an early Mid1 expression confers vulnerability to motor neurons, at least by inducing axonogenesis defects, in SBMA.
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Affiliation(s)
- Yosuke Ogura
- grid.27476.300000 0001 0943 978XDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kentaro Sahashi
- grid.27476.300000 0001 0943 978XDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tomoki Hirunagi
- grid.27476.300000 0001 0943 978XDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Madoka Iida
- grid.27476.300000 0001 0943 978XDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Takaki Miyata
- grid.27476.300000 0001 0943 978XDepartment of Anatomy and Cell Biology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahisa Katsuno
- grid.27476.300000 0001 0943 978XDepartment of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan ,grid.27476.300000 0001 0943 978XDepartment of Clinical Research Education, Nagoya University Graduate School of Medicine, Nagoya, Japan
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19
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TRAP1 in Oxidative Stress and Neurodegeneration. Antioxidants (Basel) 2021; 10:antiox10111829. [PMID: 34829705 PMCID: PMC8614808 DOI: 10.3390/antiox10111829] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 12/22/2022] Open
Abstract
Tumor necrosis factor receptor-associated protein 1 (TRAP1), also known as heat shock protein 75 (HSP75), is a member of the heat shock protein 90 (HSP90) chaperone family that resides mainly in the mitochondria. As a mitochondrial molecular chaperone, TRAP1 supports protein folding and contributes to the maintenance of mitochondrial integrity even under cellular stress. TRAP1 is a cellular regulator of mitochondrial bioenergetics, redox homeostasis, oxidative stress-induced cell death, apoptosis, and unfolded protein response (UPR) in the endoplasmic reticulum (ER). TRAP1 has attracted increasing interest as a therapeutical target, with a special focus on the design of TRAP1 specific inhibitors. Although TRAP1 was extensively studied in the oncology field, its role in central nervous system cells, under physiological and pathological conditions, remains largely unknown. In this review, we will start by summarizing the biology of TRAP1, including its structure and related pathways. Thereafter, we will continue by debating the role of TRAP1 in the maintenance of redox homeostasis and protection against oxidative stress and apoptosis. The role of TRAP1 in neurodegenerative disorders will also be discussed. Finally, we will review the potential of TRAP1 inhibitors as neuroprotective drugs.
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20
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Hsp90 Inhibition: A Promising Therapeutic Approach for ARSACS. Int J Mol Sci 2021; 22:ijms222111722. [PMID: 34769152 PMCID: PMC8584178 DOI: 10.3390/ijms222111722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/11/2021] [Accepted: 10/19/2021] [Indexed: 12/30/2022] Open
Abstract
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disease caused by mutations in the SACS gene, encoding the 520 kDa modular protein sacsin, which comprises multiple functional sequence domains that suggest a role either as a scaffold in protein folding or in proteostasis. Cells from patients with ARSACS display a distinct phenotype including altered organisation of the intermediate filament cytoskeleton and a hyperfused mitochondrial network where mitochondrial respiration is compromised. Here, we used vimentin bundling as a biomarker of sacsin function to test the therapeutic potential of Hsp90 inhibition with the C-terminal-domain-targeted compound KU-32, which has demonstrated mitochondrial activity. This study shows that ARSACS patient cells have significantly increased vimentin bundling compared to control, and this was also present in ARSACS carriers despite them being asymptomatic. We found that KU-32 treatment significantly reduced vimentin bundling in carrier and patient cells. We also found that cells from patients with ARSACS were unable to maintain mitochondrial membrane potential upon challenge with mitotoxins, and that the electron transport chain function was restored upon KU-32 treatment. Our preliminary findings presented here suggest that targeting the heat-shock response by Hsp90 inhibition alleviates vimentin bundling and may represent a promising area for the development of therapeutics for ARSACS.
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21
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Poitras TM, Munchrath E, Zochodne DW. Neurobiological Opportunities in Diabetic Polyneuropathy. Neurotherapeutics 2021; 18:2303-2323. [PMID: 34935118 PMCID: PMC8804062 DOI: 10.1007/s13311-021-01138-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/01/2021] [Indexed: 12/29/2022] Open
Abstract
This review highlights a selection of potential translational directions for the treatment of diabetic polyneuropathy (DPN) currently irreversible and without approved interventions beyond pain management. The list does not include all diabetic targets that have been generated over several decades of research but focuses on newer work. The emphasis is firstly on approaches that support the viability and growth of peripheral neurons and their ability to withstand a barrage of diabetic alterations. We include a section describing Schwann cell targets and finally how mitochondrial damage has been a common element in discussing neuropathic damage. Most of the molecules and pathways described here have not yet reached clinical trials, but many trials have been negative to date. Nonetheless, these failures clear the pathway for new thoughts over reversing DPN.
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Affiliation(s)
- Trevor M Poitras
- Peripheral Nerve Research Laboratory, Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, 7-132A Clinical Sciences Building, 11350-83 Ave, Edmonton, AB, T6G 2G3, Canada
| | - Easton Munchrath
- Peripheral Nerve Research Laboratory, Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, 7-132A Clinical Sciences Building, 11350-83 Ave, Edmonton, AB, T6G 2G3, Canada
| | - Douglas W Zochodne
- Peripheral Nerve Research Laboratory, Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, 7-132A Clinical Sciences Building, 11350-83 Ave, Edmonton, AB, T6G 2G3, Canada.
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22
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Gomez CR. Role of heat shock proteins in aging and chronic inflammatory diseases. GeroScience 2021; 43:2515-2532. [PMID: 34241808 PMCID: PMC8599533 DOI: 10.1007/s11357-021-00394-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 05/24/2021] [Indexed: 01/01/2023] Open
Abstract
Advanced age is associated with a decline in response to stress. This contributes to the establishment of chronic inflammation, one of the hallmarks of aging and age-related disease. Heat shock proteins (HSP) are determinants of life span, and their progressive malfunction leads to age-related pathology. To discuss the function of HSP on age-related chronic inflammation and illness. An updated review of literature and discussion of relevant work on the topic of HSP in normal aging and chronic inflammatory pathology was performed. HSP contribute to inflamm-aging. They also play a key role in age-associated pathology linked to chronic inflammation such as autoimmune disorders, neurological disease, cardiovascular disorder, and cancer. HSP may be targeted for control of their effects related to age and chronic inflammation. Research on HSP functions in age-linked chronic inflammatory disorders provides an opportunity to improve health span and delay age-related chronic disorders.
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Affiliation(s)
- Christian R Gomez
- Department of Pathology, University of Mississippi Medical Cent, er, 2500 N. State St, Jackson, MS, 39216, USA.
- Department of Radiation Oncology, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA.
- Preclinical Research Unit, Center for Clinical and Translational Science, University of Mississippi, 2500 N. State St, Jackson, MS, 39216, USA.
- Cancer Center and Research Institute, University of Mississippi Medical Center, 2500 N. State St, Jackson, MS, 39216, USA.
- Division of Lung Diseases, National Institutes of Health (NIH), National Heart, Lung and Blood Institute (NHLBI), Bethesda, MD, USA.
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Zhao T, Siu IM, Williamson T, Zhang H, Ji C, Burger PC, Connis N, Ruzevick J, Xia M, Cottone L, Flanagan AM, Hann CL, Gallia GL. AZD8055 enhances in vivo efficacy of afatinib in chordomas. J Pathol 2021; 255:72-83. [PMID: 34124783 DOI: 10.1002/path.5739] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 05/17/2021] [Accepted: 06/09/2021] [Indexed: 01/02/2023]
Abstract
Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Tianna Zhao
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - I-Mei Siu
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Tara Williamson
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Haoyu Zhang
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Chenchen Ji
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Peter C Burger
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nick Connis
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jacob Ruzevick
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Menghang Xia
- National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD, USA
| | - Lucia Cottone
- Department of Pathology, UCL Cancer Institute, University College London, London, UK
| | - Adrienne M Flanagan
- Department of Pathology, UCL Cancer Institute, University College London, London, UK.,Histopathology Department, Royal National Orthopaedic Hospital, Stanmore, UK
| | - Christine L Hann
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Gary L Gallia
- Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.,Department of Otolaryngology/Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Abstract
Background Ocular adverse events are common dose-limiting toxicities in cancer patients treated with HSP90 inhibitors, such as AUY922; however, the pathology and molecular mechanisms that mediate AUY922-induced retinal toxicity remain undescribed. Methods The impact of AUY922 on mouse retinas and cell lines was comprehensively investigated using isobaric tags for relative and absolute quantitation (iTRAQ)‑based proteomic profiling and pathway enrichment analysis, immunohistochemistry and immunofluorescence staining, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, MTT assay, colony formation assay, and western blot analysis. The effect of AUY922 on the Transient Receptor Potential cation channel subfamily M member 1 (TRPM1)-HSP90 chaperone complex was characterized by coimmunoprecipitation. TRPM1-regulated gene expression was analyzed by RNAseq analysis and gene set enrichment analysis (GSEA). The role of TRPM1 was assessed using both loss-of-function and gain-of-function approaches. Results Here, we show that the treatment with AUY922 induced retinal damage and cell apoptosis, dysregulated the photoreceptor and retinal pigment epithelium (RPE) layers, and reduced TRPM1 expression. Proteomic profiling and functional annotation of differentially expressed proteins reveals that those related to stress responses, protein folding processes, regulation of apoptosis, cell cycle and growth, reactive oxygen species (ROS) response, cell junction assembly and adhesion regulation, and proton transmembrane transport were significantly enriched in AUY922-treated cells. We found that AUY922 triggered caspase-3-dependent cell apoptosis, increased ROS production and inhibited cell growth. We determined that TRPM1 is a bona fide HSP90 client and characterized that AUY922 may reduce TRPM1 expression by disrupting the CDC37-HSP90 chaperone complex. Additionally, GSEA revealed that TRPM1-regulated genes were associated with retinal morphogenesis in camera-type eyes and the JAK-STAT cascade. Finally, gain-of-function and loss-of-function analyses validated the finding that TRPM1 mediated the cell apoptosis, ROS production and growth inhibition induced by AUY922. Conclusions Our study demonstrates the pathology of AUY922-induced retinal toxicity in vivo. TRPM1 is an HSP90 client, regulates photoreceptor morphology and function, and mediates AUY922-induced cytotoxicity. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-021-00751-5.
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25
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Loi M, Gennaccaro L, Fuchs C, Trazzi S, Medici G, Galvani G, Mottolese N, Tassinari M, Rimondini Giorgini R, Milelli A, Ciani E. Treatment with a GSK-3β/HDAC Dual Inhibitor Restores Neuronal Survival and Maturation in an In Vitro and In Vivo Model of CDKL5 Deficiency Disorder. Int J Mol Sci 2021; 22:5950. [PMID: 34073043 PMCID: PMC8198396 DOI: 10.3390/ijms22115950] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/26/2021] [Accepted: 05/28/2021] [Indexed: 01/03/2023] Open
Abstract
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a rare neurodevelopmental disorder characterized by early-onset seizures and severe cognitive, motor, and visual impairments. To date there are no therapies for CDKL5 deficiency disorder (CDD). In view of the severity of the neurological phenotype of CDD patients it is widely assumed that CDKL5 may influence the activity of a variety of cellular pathways, suggesting that an approach aimed at targeting multiple cellular pathways simultaneously might be more effective for CDD. Previous findings showed that a single-target therapy aimed at normalizing impaired GSK-3β or histone deacetylase (HDAC) activity improved neurodevelopmental and cognitive alterations in a mouse model of CDD. Here we tested the ability of a first-in-class GSK-3β/HDAC dual inhibitor, Compound 11 (C11), to rescue CDD-related phenotypes. We found that C11, through inhibition of GSK-3β and HDAC6 activity, not only restored maturation, but also significantly improved survival of both human CDKL5-deficient cells and hippocampal neurons from Cdkl5 KO mice. Importantly, in vivo treatment with C11 restored synapse development, neuronal survival, and microglia over-activation, and improved motor and cognitive abilities of Cdkl5 KO mice, suggesting that dual GSK-3β/HDAC6 inhibitor therapy may have a wider therapeutic benefit in CDD patients.
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Affiliation(s)
- Manuela Loi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Laura Gennaccaro
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Claudia Fuchs
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Stefania Trazzi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Giorgio Medici
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Giuseppe Galvani
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Nicola Mottolese
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | - Marianna Tassinari
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
| | | | - Andrea Milelli
- Department for Life Quality Studies, University of Bologna, 47921 Rimini, Italy;
| | - Elisabetta Ciani
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Piazza di Porta San Donato 2, 40126 Bologna, Italy; (M.L.); (L.G.); (C.F.); (S.T.); (G.M.); (G.G.); (N.M.); (M.T.)
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Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect. Int J Mol Sci 2021; 22:ijms22115859. [PMID: 34070744 PMCID: PMC8197790 DOI: 10.3390/ijms22115859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 05/23/2021] [Accepted: 05/26/2021] [Indexed: 11/16/2022] Open
Abstract
The ClC-2 channel plays a critical role in maintaining ion homeostasis in the brain and the testis. Loss-of-function mutations in the ClC-2-encoding human CLCN2 gene are linked to the white matter disease leukodystrophy. Clcn2-deficient mice display neuronal myelin vacuolation and testicular degeneration. Leukodystrophy-causing ClC-2 mutant channels are associated with anomalous proteostasis manifesting enhanced endoplasmic reticulum (ER)-associated degradation. The molecular nature of the ER quality control system for ClC-2 protein remains elusive. In mouse testicular tissues and Leydig cells, we demonstrated that endogenous ClC-2 co-existed in the same protein complex with the molecular chaperones heat shock protein 90β (Hsp90β) and heat shock cognate protein (Hsc70), as well as the associated co-chaperones Hsp70/Hsp90 organizing protein (HOP), activator of Hsp90 ATPase homolog 1 (Aha1), and FK506-binding protein 8 (FKBP8). Further biochemical analyses revealed that the Hsp90β-Hsc70 chaperone/co-chaperone system promoted mouse and human ClC-2 protein biogenesis. FKBP8 additionally facilitated membrane trafficking of ClC-2 channels. Interestingly, treatment with the Hsp90-targeting small molecule 17-allylamino-17-demethoxygeldanamycin (17-AAG) substantially boosted ClC-2 protein expression. Also, 17-AAG effectively increased both total and cell surface protein levels of leukodystrophy-causing loss-of-function ClC-2 mutant channels. Our findings highlight the therapeutic potential of 17-AAG in correcting anomalous ClC-2 proteostasis associated with leukodystrophy.
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27
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Gomez-Paredes C, Mason MA, Taxy BA, Papadopoulou AS, Paganetti P, Bates GP. The heat shock response, determined by QuantiGene multiplex, is impaired in HD mouse models and not caused by HSF1 reduction. Sci Rep 2021; 11:9117. [PMID: 33907289 PMCID: PMC8079691 DOI: 10.1038/s41598-021-88715-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Accepted: 04/14/2021] [Indexed: 01/09/2023] Open
Abstract
Huntington's disease (HD) is a devastating neurodegenerative disorder, caused by a CAG/polyglutamine repeat expansion, that results in the aggregation of the huntingtin protein, culminating in the deposition of inclusion bodies in HD patient brains. We have previously shown that the heat shock response becomes impaired with disease progression in mouse models of HD. The disruption of this inducible arm of the proteostasis network is likely to exacerbate the pathogenesis of this protein-folding disease. To allow a rapid and more comprehensive analysis of the heat shock response, we have developed, and validated, a 16-plex QuantiGene assay that allows the expression of Hsf1 and nine heat shock genes, to be measured directly, and simultaneously, from mouse tissue. We used this QuantiGene assay to show that, following pharmacological activation in vivo, the heat shock response impairment in tibialis anterior, brain hemispheres and striatum was comparable between zQ175 and R6/2 mice. In contrast, although a heat shock impairment could be detected in R6/2 cortex, this was not apparent in the cortex from zQ175 mice. Whilst the mechanism underlying this impairment remains unknown, our data indicated that it is not caused by a reduction in HSF1 levels, as had been reported.
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Affiliation(s)
- Casandra Gomez-Paredes
- Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Michael A Mason
- Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Bridget A Taxy
- Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Aikaterini S Papadopoulou
- Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK
| | - Paolo Paganetti
- Laboratory for Biomedical Neurosciences, Neurocenter of Southern Switzerland, Ente Ospedaliero Cantonale and Faculty of Biomedical Sciences, Università Della Svizzera Italiana, Lugano, Switzerland
| | - Gillian P Bates
- Huntington's Disease Centre, Department of Neurodegenerative Disease and UK Dementia Research Institute at UCL, Queen Square Institute of Neurology, University College London, London, WC1N 3BG, UK.
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Peng YF, Lin H, Liu DC, Zhu XY, Huang N, Wei YX, Li L. Heat shock protein 90 inhibitor ameliorates pancreatic fibrosis by degradation of transforming growth factor-β receptor. Cell Signal 2021; 84:110001. [PMID: 33812911 DOI: 10.1016/j.cellsig.2021.110001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 03/29/2021] [Accepted: 03/30/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Pancreatic fibrosis increases pancreatic cancer risk in chronic pancreatitis (CP). Pancreatic stellate cells (PSCs) play a critical role in pancreatic fibrosis by transforming growth factor-β (TGFβ) has been shown to inhibit transforming growth factor-β receptor (TGFβR)-mediated Smad and no-Smad signaling pathways. Thus, the effects of Hsp90 inhibitor on pancreatic fibrosis are evaluated in CP mice, and the association between Hsp90 and biological functions of PSCs is further investigated in vitro. METHODS The effects of Hsp90 inhibitor 17AAG on pancreatic fibrosis were assessed in caerulein-induced CP mice, and primary PSCs were used to determine the role of Hsp90 inhibitor 17AAG in vitro. RESULTS We observed increased expression of Hsp90 in pancreatic tissues of caerulein-induced CP mice. Hsp90 inhibitor 17AAG ameliorated pancreatic inflammation and fibrosis in caerulein-induced CP mice. In vitro, Hsp90 inhibitor 17AAG inhibited TGFβ1-induced activation and extracellular matrix accumulation of PSCs by blocking TGFβR-mediated Smad2/3 and PI3K /Akt/GSK-3β signaling pathways.Hsp90 inhibitor 17AAG degraded TGFβRII by a ubiquitin-proteasome pathway, co-immunoprecipitation showed an interaction between Hsp90 and TGFβRII in PSCs. CONCLUSIONS The study suggests that an Hsp90 inhibitor 17AAG remarkable prevents the development of pancreatic fibrosis in caerulein-induced CP mice, and suppresses activation and extracellular matrix accumulation of PSCs in vitro. The current results provide a potential treatment strategy based on Hsp90 inhibition for pancreatic fibrosis in CP.
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Affiliation(s)
- You-Fan Peng
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China
| | - Hao Lin
- Pancreatic Research Institute, Southeast University, Nanjing, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - De-Chen Liu
- Pancreatic Research Institute, Southeast University, Nanjing, China; Department of Clinical Science and Research, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xiang-Yun Zhu
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China
| | - Nan Huang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China
| | - Ying-Xiang Wei
- Department of Ultrasonic Diagnosis, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Pancreatic Research Institute, Southeast University, Nanjing, China.
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29
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Dash R, Jahan I, Ali MC, Mitra S, Munni YA, Timalsina B, Hannan MA, Moon IS. Potential roles of natural products in the targeting of proteinopathic neurodegenerative diseases. Neurochem Int 2021; 145:105011. [PMID: 33711400 DOI: 10.1016/j.neuint.2021.105011] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 03/02/2021] [Accepted: 03/03/2021] [Indexed: 12/14/2022]
Abstract
Defective proteostasis is associated with the gradual accumulations of misfolded proteins and is a hallmark of many age-associated neurodegenerative diseases. In the aged brain, maintenance of the proteostasis network presents a substantial challenge, and its loss contributes to the onset and progression of neurological diseases associated with cognitive decline due to the generation of toxic protein aggregates, a process termed 'proteinopathy'. Emerging evidence suggests that reversing proteinopathies by boosting proteostasis might provide an effective means of preventing neurodegeneration. From this perspective, phytochemicals may play significant roles as potent modulators of the proteostasis network, as previous reports have suggested they can interact with various network components to modify pathologies and confer neuroprotection. This review focuses on some potent phytochemicals that directly or indirectly modulate the proteostasis network and on their possible molecular targets. In addition, we propose strategies for the natural product-based modulation of proteostasis machinery that target proteinopathies.
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Affiliation(s)
- Raju Dash
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Israt Jahan
- Department of Pharmacy, Faculty of Life and Earth Sciences, Jagannath University, Dhaka, 1100, Bangladesh
| | - Md Chayan Ali
- Department of Biotechnology and Genetic Engineering, Faculty of Biological Sciences, Islamic University, Kushtia, 7003, Bangladesh
| | - Sarmistha Mitra
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Yeasmin Akter Munni
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Binod Timalsina
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea
| | - Md Abdul Hannan
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea; Department of Biochemistry and Molecular Biology, Bangladesh Agricultural University, Mymensingh, 2202, Bangladesh
| | - Il Soo Moon
- Department of Anatomy, Dongguk University College of Medicine, Gyeongju, 38066, Republic of Korea.
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30
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Luo X, Jiang Y, Chen F, Wei Z, Qiu Y, Xu H, Tian G, Gong W, Yuan Y, Feng H, Zhong L, Ji N, Xu X, Sun C, Li T, Li J, Feng X, Deng P, Zeng X, Zhou M, Zhou Y, Dan H, Jiang L, Chen Q. ORAOV1-B Promotes OSCC Metastasis via the NF-κB-TNFα Loop. J Dent Res 2021; 100:858-867. [PMID: 33655785 DOI: 10.1177/0022034521996339] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Metastasis, a powerful prognostic indicator of oral squamous cell carcinoma (OSCC), is chiefly responsible for poor cancer outcomes. Despite an increasing number of studies examining the mechanisms underlying poor outcomes, the development of potent strategies is hindered by insufficient characterization of the crucial regulators. Long noncoding RNAs (lncRNAs) have recently been gaining interest as significant modulators of OSCC metastasis; however, the detailed mechanisms underlying lncRNA-mediated OSCC metastasis remain relatively uncharacterized. Here, we identified a novel alternative splice variant of oral cancer overexpressed 1 (ORAOV1), named as ORAOV1-B, which was subsequently validated as an lncRNA and correlated with OSCC lymph node metastasis; significantly increased invasion and migration were observed in ORAOV1-B-overexpressing OSCC cells. RNA pulldown and mass spectrometry identified Hsp90 as a direct target of ORAOV1-B, and cDNA microarrays suggested TNFα as a potential downstream target of ORAOV1-B. ORAOV1-B was shown to directly bind to and stabilize Hsp90, which maintains the function of client proteins, receptor-interaction protein, and IκB kinase beta, thus activating the NF-κB pathway and inducing TNFα. Additionally, TNFα reciprocally enhanced p-NF-κB-p65 and the downstream epithelial-mesenchymal transition. ORAOV1-B effects were reversed by a TNFα inhibitor, demonstrating that TNFα is essential for ORAOV1-B-regulated metastatic ability. Consistent epithelial-mesenchymal transition in the ORAOV1-B group was demonstrated via an orthotopic model. In the metastatic model, ORAOV1-B significantly contributed to OSCC-related lung metastasis. In summary, the novel splice variant ORAOV1-B is an lncRNA, which significantly potentiates OSCC invasion and metastasis by binding to Hsp90 and activating the NF-κB-TNFα loop. These findings demonstrate the versatile role of ORAOV1 family members and the significance of genes located within 11q13 in promoting OSCC. ORAOV1-B might serve as an attractive OSCC metastasis intervention target.
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Affiliation(s)
- X Luo
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - F Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- The Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Z Wei
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Qiu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - H Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - G Tian
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - W Gong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Yuan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - H Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
- XiangYa Stomatological Hospital, Central South University, Changsha, China
| | - L Zhong
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - N Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Xu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - C Sun
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - T Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - J Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Feng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - P Deng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - X Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - M Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Y Zhou
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - H Dan
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - L Jiang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Q Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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Pastvova N, Dolezel P, Mlejnek P. Heat Shock Protein Inhibitor 17-Allyamino-17-Demethoxygeldanamycin, a Potent Inductor of Apoptosis in Human Glioma Tumor Cell Lines, Is a Weak Substrate for ABCB1 and ABCG2 Transporters. Pharmaceuticals (Basel) 2021; 14:ph14020107. [PMID: 33573093 PMCID: PMC7912456 DOI: 10.3390/ph14020107] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 01/26/2021] [Accepted: 01/26/2021] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a poor prognosis. Complex genetic alterations and the protective effect of the blood–brain barrier (BBB) have so far hampered effective treatment. Here, we investigated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors, geldanamycin (GDN) and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), in a panel of glioma tumor cell lines with various genetic alterations. We also assessed the ability of the main drug transporters, ABCB1 and ABCG2, to efflux GDN and 17-AAG. We found that GDN and 17-AAG induced extensive cell death with the morphological and biochemical hallmarks of apoptosis in all studied glioma cell lines at sub-micro-molar and nanomolar concentrations. Moderate efflux efficacy of GDN and 17-AAG mediated by ABCB1 was observed. There was an insignificant and low efflux efficacy of GDN and 17-AAG mediated by ABCG2. Conclusion: GDN and 17-AAG, in particular, exhibited strong proapoptotic effects in glioma tumor cell lines irrespective of genetic alterations. GDN and 17-AAG appeared to be weak substrates of ABCB1 and ABCG2. Therefore, the BBB would compromise their cytotoxic effects only partially. We hypothesize that GBM patients may benefit from 17-AAG either as a single agent or in combination with other drugs.
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Hervás R, Oroz J. Mechanistic Insights into the Role of Molecular Chaperones in Protein Misfolding Diseases: From Molecular Recognition to Amyloid Disassembly. Int J Mol Sci 2020; 21:ijms21239186. [PMID: 33276458 PMCID: PMC7730194 DOI: 10.3390/ijms21239186] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 11/29/2020] [Accepted: 11/29/2020] [Indexed: 12/14/2022] Open
Abstract
Age-dependent alterations in the proteostasis network are crucial in the progress of prevalent neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, or amyotrophic lateral sclerosis, which are characterized by the presence of insoluble protein deposits in degenerating neurons. Because molecular chaperones deter misfolded protein aggregation, regulate functional phase separation, and even dissolve noxious aggregates, they are considered major sentinels impeding the molecular processes that lead to cell damage in the course of these diseases. Indeed, members of the chaperome, such as molecular chaperones and co-chaperones, are increasingly recognized as therapeutic targets for the development of treatments against degenerative proteinopathies. Chaperones must recognize diverse toxic clients of different orders (soluble proteins, biomolecular condensates, organized protein aggregates). It is therefore critical to understand the basis of the selective chaperone recognition to discern the mechanisms of action of chaperones in protein conformational diseases. This review aimed to define the selective interplay between chaperones and toxic client proteins and the basis for the protective role of these interactions. The presence and availability of chaperone recognition motifs in soluble proteins and in insoluble aggregates, both functional and pathogenic, are discussed. Finally, the formation of aberrant (pro-toxic) chaperone complexes will also be disclosed.
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Affiliation(s)
- Rubén Hervás
- Stowers Institute for Medical Research, Kansas City, MO 64110, USA;
| | - Javier Oroz
- Rocasolano Institute for Physical Chemistry, Spanish National Research Council (IQFR-CSIC), Serrano 119, E-28006 Madrid, Spain
- Correspondence: ; Tel.: +34-915619400
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Hashizume A, Fischbeck KH, Pennuto M, Fratta P, Katsuno M. Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA). J Neurol Neurosurg Psychiatry 2020; 91:1085-1091. [PMID: 32934110 DOI: 10.1136/jnnp-2020-322949] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 07/10/2020] [Accepted: 07/27/2020] [Indexed: 12/13/2022]
Abstract
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.
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MESH Headings
- 5-alpha Reductase Inhibitors/therapeutic use
- Adipose Tissue/diagnostic imaging
- Adrenergic beta-Agonists/therapeutic use
- Autophagy
- Biomarkers
- Bulbo-Spinal Atrophy, X-Linked/diagnostic imaging
- Bulbo-Spinal Atrophy, X-Linked/metabolism
- Bulbo-Spinal Atrophy, X-Linked/physiopathology
- Bulbo-Spinal Atrophy, X-Linked/therapy
- Clenbuterol/therapeutic use
- Creatinine/metabolism
- Dutasteride/therapeutic use
- Glycolysis
- Humans
- Insulin-Like Growth Factor I/analogs & derivatives
- Leuprolide/therapeutic use
- Magnetic Resonance Imaging
- Mitochondria/metabolism
- Muscle Fibers, Fast-Twitch/metabolism
- Muscle Fibers, Fast-Twitch/pathology
- Muscle Fibers, Slow-Twitch/metabolism
- Muscle Fibers, Slow-Twitch/pathology
- Muscle, Skeletal/diagnostic imaging
- Muscle, Skeletal/metabolism
- Muscle, Skeletal/pathology
- Oligonucleotides, Antisense/therapeutic use
- Oxidation-Reduction
- RNAi Therapeutics
- Receptors, Androgen/genetics
- Receptors, Androgen/metabolism
- Trinucleotide Repeat Expansion
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Affiliation(s)
- Atsushi Hashizume
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
| | - Kenneth H Fischbeck
- Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
| | - Maria Pennuto
- Department of Biomedical Sciences (DBS), University of Padova, Padova, Italy
- Veneto Institute of Molecular Medicine (VIMM), Padova, Italy
| | - Pietro Fratta
- Depatment of Neuromuscular Diseases, University College London Institute of Neurology, London, UK
- MRC Centre for Neuromuscular Diseases, University College London Institute of Neurology, London, UK
| | - Masahisa Katsuno
- Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
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Limanaqi F, Busceti CL, Biagioni F, Cantini F, Lenzi P, Fornai F. Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA. Int J Mol Sci 2020; 21:ijms21114021. [PMID: 32512809 PMCID: PMC7312203 DOI: 10.3390/ijms21114021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/29/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022] Open
Abstract
The coordinated activities of autophagy and the ubiquitin proteasome system (UPS) are key to preventing the aggregation and toxicity of misfold-prone proteins which manifest in a number of neurodegenerative disorders. These include proteins which are encoded by genes containing nucleotide repeat expansions. In the present review we focus on the overlapping role of autophagy and the UPS in repeat expansion proteotoxicity associated with chromosome 9 open reading frame 72 (C9ORF72) and androgen receptor (AR) genes, which are implicated in two motor neuron disorders, amyotrophic lateral sclerosis (ALS) and spinal-bulbar muscular atrophy (SBMA), respectively. At baseline, both C9ORF72 and AR regulate autophagy, while their aberrantly-expanded isoforms may lead to a failure in both autophagy and the UPS, further promoting protein aggregation and toxicity within motor neurons and skeletal muscles. Besides proteotoxicity, autophagy and UPS alterations are also implicated in neuromuscular junction (NMJ) alterations, which occur early in both ALS and SBMA. In fact, autophagy and the UPS intermingle with endocytic/secretory pathways to regulate axonal homeostasis and neurotransmission by interacting with key proteins which operate at the NMJ, such as agrin, acetylcholine receptors (AChRs), and adrenergic beta2 receptors (B2-ARs). Thus, alterations of autophagy and the UPS configure as a common hallmark in both ALS and SBMA disease progression. The findings here discussed may contribute to disclosing overlapping molecular mechanisms which are associated with a failure in cell-clearing systems in ALS and SBMA.
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Affiliation(s)
- Fiona Limanaqi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (F.L.); (F.C.); (P.L.)
| | | | - Francesca Biagioni
- I.R.C.C.S. Neuromed, Via Atinense, 18, 86077 Pozzilli, Italy; (C.L.B.); (F.B.)
| | - Federica Cantini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (F.L.); (F.C.); (P.L.)
| | - Paola Lenzi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (F.L.); (F.C.); (P.L.)
| | - Francesco Fornai
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy; (F.L.); (F.C.); (P.L.)
- I.R.C.C.S. Neuromed, Via Atinense, 18, 86077 Pozzilli, Italy; (C.L.B.); (F.B.)
- Correspondence:
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Liu M, Li M, Zhou Y, Zhou Q, Jiang Y. HSP90 inhibitor 17AAG attenuates sevoflurane-induced neurotoxicity in rats and human neuroglioma cells via induction of HSP70. J Transl Med 2020; 18:166. [PMID: 32293462 PMCID: PMC7158111 DOI: 10.1186/s12967-020-02332-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 04/06/2020] [Indexed: 12/23/2022] Open
Abstract
Background 17AAG has been extensively studied for its antitumor effects that protect cells from lethal stress by maintaining protein stability. The role of 17AAG in sevoflurane-induced neuronal injury has never been studied. We aim to investigate the effect of 17AAG on sevoflurane-induced neurotoxicity in vivo and in vitro. Methods Sevoflurane-induced hippocampal neuron injury model was established in aged Sprague–Dawley rats. Pretreatment of vehicle or 17AAG was administered prior to sevoflurane inhalation. H4 neuroglioma cells were pretreated with vehicle or 17AAG and exposed to sevoflurane. Apoptosis, oxidative stress, expression of interleukin-6 (IL-6), and activation of the nuclear factor-κB (NF-κB) signaling pathway in H4 cells were examined by Hoechst assay, flow cytometry, Western blot, and immunofluorescent staining. RNA interference against HSPA1A was performed to test the function of HSP70 in neuroprotection. Results Exogenous 17AAG reduced sevoflurane-induced apoptosis and oxidative stress in rat hippocampal neurons and in H4 cells. In H4 cells, 17AAG suppressed sevoflurane-induced upregulation of IL-6 and activation of NF-κB signaling. 17AAG enhanced sevoflurane-induced upregulation of HSP70 in rat hippocampal neurons and in H4 cells. Conversely, silencing of HSPA1A in H4 cells blocked the cytoprotective effect of 17AAG against sevoflurane-induced apoptosis and oxidative stress, and prevented upregulation of IL-6 and activation of NF-κB signaling. Conclusions 17AAG protects against sevoflurane-induced neurotoxicity in vivo and in vitro via HSP70-dependent inhibition of apoptosis, oxidative stress, and pro-inflammatory signaling pathway.
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Affiliation(s)
- Min Liu
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, No. 139, Changsha City, 410000, Hunan Province, People's Republic of China
| | - Moyun Li
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha City, 410000, Hunan Province, People's Republic of China
| | - Yu Zhou
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, No. 139, Changsha City, 410000, Hunan Province, People's Republic of China
| | - Qian Zhou
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, No. 139, Changsha City, 410000, Hunan Province, People's Republic of China
| | - Yugang Jiang
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, No. 139, Changsha City, 410000, Hunan Province, People's Republic of China.
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Zhang Y, Zhou P, Wang Z, Chen M, Fu F, Su R. Hsp90β positively regulates μ-opioid receptor function. Life Sci 2020; 252:117676. [PMID: 32304763 DOI: 10.1016/j.lfs.2020.117676] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 03/29/2020] [Accepted: 04/13/2020] [Indexed: 01/19/2023]
Abstract
AIMS Many μ-opioid receptor (MOR)-associated proteins can regulate the MOR signaling pathway. Using a bacterial two-hybrid screen, we found that the C-terminal of the MOR associated with heat shock protein 90 isoform β (Hsp90β). Here, we explored the effect of Hsp90β on MOR signaling transduction and function. MAIN METHODS The interaction of Hsp90β with MOR was detected by co-immunoprecipitation and immunofluorescence. The effects of Hsp90β on MOR signaling induced by opioids were studied in vitro and in vivo. The effects of the Hsp90β inhibitor 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) on morphine tolerance and dependence were studied via a hot plate test and CPP test. KEY FINDINGS Hsp90β, instead of Hsp90α, interacted with the MOR in HEK293 cells and SH-SY5Y cells, and the interaction was augmented after morphine pretreatment. The interaction of Hsp90β and MOR increased the inhibition of cAMP and decreased PKA activity under opioid treatment. The functional Hsp90β-MOR complex also promoted the phosphorylation and internalization of the MOR induced by DAMGO in MOR-CHO cells. 17-AAG blocked Hsp90β-MOR interactions and decreased the effect of Hsp90β on the MOR signal transduction. In C57BL/6 mice, 17-AAG decreased morphine-induced acute anti-nociception in the hot plate test, with an increase in phosphorylated PKA and phosphorylated JNK and a decrease in phosphorylated CREB and phosphorylated ERK in murine brains. Chronic morphine treatment induced tolerance, and dependence was inhibited by 17-AAG co-administration. SIGNIFICANCE Hsp90β is a positive co-regulator of the MOR via the activation of a G-protein-dependent and β-arrestin-dependent pathway. Hsp90β has the potential to improve the pharmacologic profile of existing opiates. It is conceivable that in future clinical treatments, the Hsp90β inhibitor, 17-AAG, could decrease the tolerance and dependence in cancer patients induced by opioids.
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Affiliation(s)
- Yixin Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China
| | - Peilan Zhou
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China
| | - Zhen Wang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China; School of Pharmacy, Yantai University, Yantai 264005, China
| | - Ming Chen
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China
| | - Fenghua Fu
- School of Pharmacy, Yantai University, Yantai 264005, China
| | - Ruibin Su
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing Institute of Pharmacology and Toxicology, 27th Taiping Road, Beijing 100850, China.
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Jeng CJ, Fu SJ, You CY, Peng YJ, Hsiao CT, Chen TY, Tang CY. Defective Gating and Proteostasis of Human ClC-1 Chloride Channel: Molecular Pathophysiology of Myotonia Congenita. Front Neurol 2020; 11:76. [PMID: 32117034 PMCID: PMC7026490 DOI: 10.3389/fneur.2020.00076] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 01/22/2020] [Indexed: 01/17/2023] Open
Abstract
The voltage-dependent ClC-1 chloride channel, whose open probability increases with membrane potential depolarization, belongs to the superfamily of CLC channels/transporters. ClC-1 is almost exclusively expressed in skeletal muscles and is essential for stabilizing the excitability of muscle membranes. Elucidation of the molecular structures of human ClC-1 and several CLC homologs provides important insight to the gating and ion permeation mechanisms of this chloride channel. Mutations in the human CLCN1 gene, which encodes the ClC-1 channel, are associated with a hereditary skeletal muscle disease, myotonia congenita. Most disease-causing CLCN1 mutations lead to loss-of-function phenotypes in the ClC-1 channel and thus increase membrane excitability in skeletal muscles, consequently manifesting as delayed relaxations following voluntary muscle contractions in myotonic subjects. The inheritance pattern of myotonia congenita can be autosomal dominant (Thomsen type) or recessive (Becker type). To date over 200 myotonia-associated ClC-1 mutations have been identified, which are scattered throughout the entire protein sequence. The dominant inheritance pattern of some myotonia mutations may be explained by a dominant-negative effect on ClC-1 channel gating. For many other myotonia mutations, however, no clear relationship can be established between the inheritance pattern and the location of the mutation in the ClC-1 protein. Emerging evidence indicates that the effects of some mutations may entail impaired ClC-1 protein homeostasis (proteostasis). Proteostasis of membrane proteins comprises of biogenesis at the endoplasmic reticulum (ER), trafficking to the surface membrane, and protein turn-over at the plasma membrane. Maintenance of proteostasis requires the coordination of a wide variety of different molecular chaperones and protein quality control factors. A number of regulatory molecules have recently been shown to contribute to post-translational modifications of ClC-1 and play critical roles in the ER quality control, membrane trafficking, and peripheral quality control of this chloride channel. Further illumination of the mechanisms of ClC-1 proteostasis network will enhance our understanding of the molecular pathophysiology of myotonia congenita, and may also bring to light novel therapeutic targets for skeletal muscle dysfunction caused by myotonia and other pathological conditions.
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Affiliation(s)
- Chung-Jiuan Jeng
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Brain Research Center, National Yang-Ming University, Taipei, Taiwan
| | - Ssu-Ju Fu
- Institute of Anatomy and Cell Biology, School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chia-Ying You
- Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Yi-Jheng Peng
- Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Tsung Hsiao
- Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.,Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tsung-Yu Chen
- Center for Neuroscience, University of California, Davis, Davis, CA, United States
| | - Chih-Yung Tang
- Department of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan.,College of Medicine, Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan
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Gupta A, Bansal A, Hashimoto-Torii K. HSP70 and HSP90 in neurodegenerative diseases. Neurosci Lett 2020; 716:134678. [PMID: 31816334 PMCID: PMC7336893 DOI: 10.1016/j.neulet.2019.134678] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/27/2019] [Accepted: 12/05/2019] [Indexed: 12/11/2022]
Abstract
Molecular chaperones have a role to stabilize proteins or assist them in reaching their native fold. Heat shock proteins (HSPs) are a family of molecular chaperons that protect proteins from cellular stress during the assembly of protein complexes and also prevent the proteins from aggregation and disassembly. The immediate increase of HSPs is crucial for cellular adaptation to environmental changes and protection of other proteins from denaturation, thereby maintaining the cellular homeostasis and increasing the longevity of an organism. HSP70 and HSP90 are the most studied HSPs in this very large HSP family. Notably, HSP90 also stabilizes the disease-related proteins in neurodegenerative disorders. Therefore, small molecules that inhibit the HSP90 but also increase the HSP70 has been tested as potential drugs for neurodegenerative disorders.
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Affiliation(s)
- Abha Gupta
- University Institute of Biotechnology, Chandigarh University, Gharuan, 140413, India
| | - Ankush Bansal
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA.
| | - Kazue Hashimoto-Torii
- Center for Neuroscience Research, Children's Research Institute, Children's National Hospital, Washington, DC 20010, USA; Department of Pediatrics, School of Medicine and Health Sciences, The George Washington University, Washington, DC, 20052, USA.
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Jung S, Yoon NG, Yang S, Kim D, Lee WS, Hong KB, Lee C, Kang BH, Lee JH, Kang S. Discovery of 2-((4-resorcinolyl)-5-aryl-1,2,3-triazol-1-yl)acetates as potent Hsp90 inhibitors with selectivity over TRAP1. Bioorg Med Chem Lett 2020; 30:126809. [DOI: 10.1016/j.bmcl.2019.126809] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 10/29/2019] [Accepted: 11/04/2019] [Indexed: 12/11/2022]
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Umme Hani, Kandagalla S, Sharath BS, Jyothsna K, Manjunatha H. Network Pharmacology Approach Uncovering Pathways Involved in Targeting Hsp90 Through Curcumin and Epigallocatechin to Control Inflammation. Curr Drug Discov Technol 2019; 18:127-138. [PMID: 31820701 DOI: 10.2174/1570163816666191210145652] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 10/07/2019] [Accepted: 10/15/2019] [Indexed: 11/22/2022]
Abstract
AIMS To fetch pathways involved in targetting Hsp90 through Curcumin and Epigallocatechin through Network pharmacological approach. BACKGROUND Hsp90 is a molecular chaperone involved in stabilizing inflammatory protein which may lead to chronic diseases. The herbal compounds Curcumin and Epigallocatechin processing antiinflammatory properties are known to follow a common pathway and control the expression of Hsp90. OBJECTIVE To collect the gene targets of Hsp90, Curcumin and Epigallocatechin in order to understand protein-protein interactions of gene targets by constructing the interactome to identify the hub proteins. Hub proteins docking was performed with curcumin and epigallocatechin. Finally, hub proteins involvement with various human diseases were identified. METHODS The gene targets of Hsp90, Curcumin and Epigallocatechin were obtained from there respective databases. Protein-protein interactions of Pkcδ-Nrf2 and Tlr4 pathway gene targets were collected from String database. Protein interaction network was constructed and merged to get intercession network in cytoscape and Cluego was used to predict the disease related target genes. Docking of ligands to target proteins was carried out using Autodock vina tool. RESULT The main key regulators of Curcumin and Epigallocatechin were identified particularly from Pkcδ-Nrf2 and Tlr4 pathway. CONCLUSION The combined action of Curcumin and Epigallocatechin can reduce the expression of Hsp90 eventually controlling the inflammation.
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Affiliation(s)
- Umme Hani
- Department of Biotechnology, Janana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka 577451, India
| | - Shivananda Kandagalla
- Department of Biotechnology, Janana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka 577451, India
| | - B S Sharath
- Department of Biotechnology, Janana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka 577451, India
| | - K Jyothsna
- Department of Biotechnology, Janana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka 577451, India
| | - Hanumanthappa Manjunatha
- Department of Biotechnology, Janana Sahyadri, Kuvempu University, Shankaraghatta, Shivamogga, Karnataka 577451, India
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Calabrese EJ, Bhatia TN, Calabrese V, Dhawan G, Giordano J, Hanekamp YN, Kapoor R, Kozumbo WJ, Leak RK. Cytotoxicity models of Huntington’s disease and relevance of hormetic mechanisms: A critical assessment of experimental approaches and strategies. Pharmacol Res 2019; 150:104371. [DOI: 10.1016/j.phrs.2019.104371] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 12/17/2022]
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Iida M, Sahashi K, Kondo N, Nakatsuji H, Tohnai G, Tsutsumi Y, Noda S, Murakami A, Onodera K, Okada Y, Nakatochi M, Tsukagoshi Okabe Y, Shimizu S, Mizuno M, Adachi H, Okano H, Sobue G, Katsuno M. Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy. Nat Commun 2019; 10:4262. [PMID: 31537808 PMCID: PMC6753158 DOI: 10.1038/s41467-019-12282-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2018] [Accepted: 08/29/2019] [Indexed: 12/12/2022] Open
Abstract
Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.
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Affiliation(s)
- Madoka Iida
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
- Japan Society for the Promotion of Science, 5-3-1, Kojimachi, Chiyoda-ku, Tokyo, 102-0083, Japan
| | - Kentaro Sahashi
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Naohide Kondo
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Hideaki Nakatsuji
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Genki Tohnai
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Yutaka Tsutsumi
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Seiya Noda
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
- Department of Neurology, National Hospital Organization Suzuka National Hospital, 3-2-1, Kasado, Suzuka city, Mie, 513-8501, Japan
| | - Ayuka Murakami
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
- Department of Neurology, National Hospital Organization Suzuka National Hospital, 3-2-1, Kasado, Suzuka city, Mie, 513-8501, Japan
| | - Kazunari Onodera
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
- Department of Neurology, Aichi Medical University School of Medicine, 1, Karimata, Yazako, Nagakute-city, Aichi, 480-1195, Japan
| | - Yohei Okada
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
- Department of Neurology, Aichi Medical University School of Medicine, 1, Karimata, Yazako, Nagakute-city, Aichi, 480-1195, Japan
- Department of Physiology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Masahiro Nakatochi
- Department of Nursing, Nagoya University Graduate School of Medicine, 1-1-20 Daiko-Minami, Higashi-ku, Nagoya city, Aichi, 461-8673, Japan
| | - Yuka Tsukagoshi Okabe
- Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8560, Japan
| | - Shinobu Shimizu
- Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8560, Japan
| | - Masaaki Mizuno
- Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8560, Japan
| | - Hiroaki Adachi
- Department of Neurology, University of Occupational and Environmental Health School of Medicine, 1-1, Iseigaoka, Yahatanichi-ku, Kitakyushu-city, Fukuoka, 807-0804, Japan
| | - Hideyuki Okano
- Department of Physiology, Keio University School of Medicine, 35, Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan
| | - Gen Sobue
- Brain and Mind Research Center, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan
| | - Masahisa Katsuno
- Department of Neurology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya city, Aichi, 466-8550, Japan.
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Clarke BE, Gil RS, Yip J, Kalmar B, Greensmith L. Regional differences in the inflammatory and heat shock response in glia: implications for ALS. Cell Stress Chaperones 2019; 24:857-870. [PMID: 31168740 PMCID: PMC6717175 DOI: 10.1007/s12192-019-01005-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/03/2019] [Accepted: 05/04/2019] [Indexed: 12/11/2022] Open
Abstract
Preferential neuronal vulnerability is characteristic of several neurodegenerative diseases including the motor neuron disease amyotrophic lateral sclerosis (ALS). It is well established that glia play a critical role in ALS, but it is unknown whether regional differences in the ability of glia to support motor neurons contribute to the specific pattern of neuronal degeneration. In this study, using primary mixed glial cultures from different mouse CNS regions (spinal cord and cortex), we examined whether regional differences exist in key glial pathways that contribute to, or protect against, motor neuron degeneration. Specifically, we examined the NF-κB-mediated inflammatory pathway and the cytoprotective heat shock response (HSR). Glial cultures were treated with pro-inflammatory stimuli, tumour necrosis factor-ɑ/lipopolysaccharide or heat stressed to stimulate the inflammatory and HSR respectively. We found that spinal cord glia expressed more iNOS and produced more NO compared to cortical glia in response to inflammatory stimuli. Intriguingly, we found that expression of ALS-causing SOD1G93A did not elevate the levels of NO in spinal cord glia. However, activation of the stress-responsive HSR was attenuated in SOD1G93A cultures, with a reduced Hsp70 induction in response to stressful stimuli. Exposure of spinal cord glia to heat shock in combination with inflammatory stimuli reduced the activation of the inflammatory response. The results of this study suggest that impaired heat shock response in SOD1G93A glia may contribute to the exacerbated inflammatory reactions observed in ALS mice. Graphical abstract Mixed primary glial cultures were established from cortical and spinal cord regions of wild-type mice and mice expressing ALS-causing mutant human SOD1 and the inflammatory and heat shock responses were investigated in these cultures. In the absence of stress, all cultures appeared to have similar cellular composition, levels of inflammatory mediators and similar expression level of heat shock proteins. When stimulated, spinal cord glia were more reactive and activated the inflammatory pathway more readily than cortical glia; this response was similar in wild-type and SOD1G93A glial cultures. Although the heat shock response was similar in spinal cord and cortical glial, in SOD1G93A expressing glia from both the spinal cord and cortex, the induction of heat shock response was diminished. This impaired heat shock response in SOD1G93A glia may therefore contribute to the exacerbated inflammatory reactions observed in ALS mice.
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Affiliation(s)
- Benjamin E Clarke
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- MRC Centre for Neuromuscular Disease, London, WC1N 3BG, UK
| | - Rebecca San Gil
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Northfields Ave, Wollongong, 2522, Australia
| | - Jing Yip
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
| | - Bernadett Kalmar
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK.
| | - Linda Greensmith
- Department of Neuromuscular Diseases, University College London (UCL) Queen Square Institute of Neurology, London, WC1N 3BG, UK
- MRC Centre for Neuromuscular Disease, London, WC1N 3BG, UK
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HSP90 inhibitors stimulate DNAJB4 protein expression through a mechanism involving N 6-methyladenosine. Nat Commun 2019; 10:3613. [PMID: 31399576 PMCID: PMC6688989 DOI: 10.1038/s41467-019-11552-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 07/22/2019] [Indexed: 12/26/2022] Open
Abstract
Small-molecule inhibitors for the 90-kDa heat shock protein (HSP90) have been extensively exploited in preclinical studies for the therapeutic interventions of human diseases accompanied with proteotoxic stress. By using an unbiased quantitative proteomic method, we uncover that treatment with three HSP90 inhibitors results in elevated expression of a large number of heat shock proteins. We also demonstrate that the HSP90 inhibitor-mediated increase in expression of DNAJB4 protein occurs partly through an epitranscriptomic mechanism, and is substantially modulated by the writer, eraser, and reader proteins of N6-methyladenosine (m6A). Furthermore, exposure to ganetespib leads to elevated modification levels at m6A motif sites in the 5′-UTR of DNAJB4 mRNA, and the methylation at adenosine 114 site in the 5′-UTR promotes the translation of the reporter gene mRNA. This m6A-mediated mechanism is also at play upon heat shock treatment. Cumulatively, we unveil that HSP90 inhibitors stimulate the translation of DNAJB4 through an epitranscriptomic mechanism. Cells respond to heat shock with transcriptional and translational adaptations but how HSP90 inhibition alters the heat shock proteome is largely unclear. Here, the authors analyze proteome changes upon HSP90 inhibition and show that an m6A-mediated mechanism contributes to the heat shock-induced upregulation of DNAJB4.
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45
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Chaari A. Molecular chaperones biochemistry and role in neurodegenerative diseases. Int J Biol Macromol 2019; 131:396-411. [DOI: 10.1016/j.ijbiomac.2019.02.148] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 02/07/2023]
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46
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Sampaio-Marques B, Ludovico P. Linking cellular proteostasis to yeast longevity. FEMS Yeast Res 2019; 18:4970764. [PMID: 29800380 DOI: 10.1093/femsyr/foy043] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 04/12/2018] [Indexed: 12/19/2022] Open
Abstract
Proteostasis is a cellular housekeeping process that refers to the healthy maintenance of the cellular proteome that governs the fate of proteins from synthesis to degradation. Perturbations of proteostasis might result in protein dysfunction with consequent deleterious effects that can culminate in cell death. To deal with the loss of proteostasis, cells are supplied with a highly sophisticated and interconnected network that integrates as major players the molecular chaperones and the protein degradation pathways. It is well recognized that the ability of cells to maintain proteostasis declines during ageing, although the precise mechanisms are still elusive. Indeed, genetic or pharmacological enhancement of the proteostasis network has been shown to extend lifespan in a variety of ageing models. Therefore, an improved understanding of the interventions/mechanisms that contribute to cellular protein quality control will have a huge impact on the ageing field. This mini-review centers on the current knowledge about the major pathways that contribute for the maintenance of Saccharomyces cerevisiae proteostasis, with particular emphasis on the developments that highlight the multidimensional nature of the proteostasis network in the maintenance of proteostasis, as well as the age-dependent changes on this network.
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Affiliation(s)
- Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus Gualtar, 4710-057 Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
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47
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Zuo Y, Wang J, Liao F, Yan X, Li J, Huang L, Liu F. Inhibition of Heat Shock Protein 90 by 17-AAG Reduces Inflammation via P2X7 Receptor/NLRP3 Inflammasome Pathway and Increases Neurogenesis After Subarachnoid Hemorrhage in Mice. Front Mol Neurosci 2018; 11:401. [PMID: 30459553 PMCID: PMC6232389 DOI: 10.3389/fnmol.2018.00401] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Accepted: 10/12/2018] [Indexed: 12/23/2022] Open
Abstract
Subarachnoid hemorrhage (SAH) is a life-threatening cerebrovascular disease that usually has a poor prognosis. Heat shock proteins (HSPs) have been implicated in the mechanisms of SAH-associated damage, including increased inflammation and reduced neurogenesis. The aim of this study was to investigate the effects of HSP90 inhibition on inflammation and neurogenesis in a mouse model of experimental SAH induced by endovascular surgery. Western blotting showed HSP90 levels to be decreased, while neurogenesis, evaluated by 5-bromo-2'-deoxyuridine (BrdU) immunohistochemistry, was decreased in the hippocampuses of SAH mice. SAH also induced pro-inflammatory factors such as interleukin-1β (IL-1β), capase-1 and the NLRP3 inflammasome. However, intraperitoneal administration of the specific HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) reduced the levels of HSP90, NLRP3, ASC, caspase-1 and IL-1β, while increasing the levels of brain-derived neurotrophic factor and doublecortin (DCX), as well as the number of BrdU-positive cells in SAH mice. In addition, 17-AGG improved short- and long-term neurobehavioral outcomes. The neuroprotective and anti-inflammatory effects of 17-AGG were reversed by recombinant HSP90 (rHSP90); this detrimental effect of HSP90 was inhibited by the specific P2X7 receptor (P2X7R) inhibitor A438079, indicating that SAH-induced inflammation and inhibition of neurogenesis were likely mediated by HSP90 and the P2X7R/NLRP3 inflammasome pathway. HSP90 inhibition by 17-AAG may be a promising therapeutic strategy for the treatment of SAH.
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Affiliation(s)
- Yuchun Zuo
- Department of Neurosurgery, Third XiangYa Hospital, Central South University, Changsha, China
| | - Jikai Wang
- Department of Neurosurgery, Third XiangYa Hospital, Central South University, Changsha, China
| | - Fan Liao
- Department of Neurosurgery, Third XiangYa Hospital, Central South University, Changsha, China
| | - Xiaoxin Yan
- Department of Anatomy, XiangYa Medical School, Central South University, Changsha, China
| | - Jianming Li
- Neuroscience Research Center, Changsha Medical University, Changsha, China
| | - Lei Huang
- Department of Physiology and Pharmacology, School of Medicine, Loma Linda University, Loma Linda, CA, United States.,Department of Neurosurgery, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Fei Liu
- Department of Neurosurgery, Third XiangYa Hospital, Central South University, Changsha, China
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Nath SR, Yu Z, Gipson TA, Marsh GB, Yoshidome E, Robins DM, Todi SV, Housman DE, Lieberman AP. Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction. J Clin Invest 2018; 128:3630-3641. [PMID: 29809168 DOI: 10.1172/jci99042] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 05/24/2018] [Indexed: 12/28/2022] Open
Abstract
Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.
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Affiliation(s)
- Samir R Nath
- Department of Pathology.,Medical Scientist Training Program, and.,Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | | | - Theresa A Gipson
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - Gregory B Marsh
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | | | - Diane M Robins
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Sokol V Todi
- Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, USA
| | - David E Housman
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
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Ma L, Yang D, Li Z, Zhang X, Pu L. Co-delivery of paclitaxel and tanespimycin in lipid nanoparticles enhanced anti-gastric-tumor effect in vitro and in vivo. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2018; 46:904-911. [PMID: 29757014 DOI: 10.1080/21691401.2018.1472101] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Combined administration regimens are commonly used in cancer therapy to reduce cell toxicity and drug resistance. In this study, we use solid lipid nanoparticles (SLNs) as drug carriers and sought to investigate the effect of combined administration of paclitaxel (PTX) and tanespimycin (17-AAG) in gastric cancer. The SLNs loaded with paclitaxel and tanespimycin were prepared using the solvent injection method. The effect of encapsulated SLNs on cell viability and colony formation were measured in three human gastric cell lines. Cell apoptosis assay was carried out in MKN45 cells and xenograft model was used to investigate the effect of encapsulated SLNs in vitro and in vivo. The expression levels of proteins involved in oxidative stress and apoptosis were measured by western blotting analysis. The encapsulated SLNs reduced cell viabilities and colony formation in gastric cell lines. These SLNs could also induce apoptosis in MKN45 cells, inhibit growth of xenograft and influence the protein levels of Hsp90, MnSOD, Cleaved caspase 3 and Cleaved PARP. The effect of encapsulated SLNs exceeded that of single treatment of PTX or 17-AAG. The combination administration of PTX or 17-AAG resulted in a synergetic anti-cancer effect, probably via an increased oxidative stress and apoptosis levels.
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Affiliation(s)
- Liang Ma
- a The Central People's Hospital of Siping City , Siping , Jilin , China
| | - Dawei Yang
- a The Central People's Hospital of Siping City , Siping , Jilin , China
| | - Zhaoxin Li
- a The Central People's Hospital of Siping City , Siping , Jilin , China
| | - Xin Zhang
- a The Central People's Hospital of Siping City , Siping , Jilin , China
| | - Lei Pu
- a The Central People's Hospital of Siping City , Siping , Jilin , China
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50
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Pennuto M, Rinaldi C. From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet? Mol Cell Endocrinol 2018; 465:113-121. [PMID: 28688959 DOI: 10.1016/j.mce.2017.07.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Revised: 06/30/2017] [Accepted: 07/03/2017] [Indexed: 01/12/2023]
Abstract
Abnormal polyglutamine expansions in the androgen receptor (AR) cause a muscular condition, known as Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). The disease is transmitted in an X-linked fashion and is clinically characterized by weakness, atrophy and fasciculations of the limb and bulbar muscles as a result of a toxic gain-of-function of the mutant protein. Notably, affected males also show signs of androgen insensitivity, such as gynaecomastia and reduced fertility. The characterization of the natural history of the disease, the increasing understanding of the mechanism of pathogenesis and the elucidation of the functions of normal and mutant AR have offered a momentum for developing a rational therapeutic strategy for this disease. In this special issue on androgens and AR functions, we will review the molecular, biochemical, and cellular mechanisms underlying the pathogenesis of SBMA. We will discuss recent advances on therapeutic approaches and opportunities for this yet incurable disease, ranging from androgen deprivation, to gene silencing, to an expanding repertoire of peripheral targets, including muscle. With the advancement of these strategies into the clinic, it can be reasonably anticipated that the landscape of treatment options for SBMA and other neuromuscular conditions will change rapidly in the near future.
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Affiliation(s)
- Maria Pennuto
- Dulbecco Telethon Institute, Centre for Integrative Biology, University of Trento, 38123 Trento, Italy; Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
| | - Carlo Rinaldi
- Department of Physiology, Anatomy and Genetics, University of Oxford, OX1 3QX Oxford, UK.
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