期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 116, 期 48, 页码 24310-24316出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1903268116
关键词
Lewy body; chaperone; synapse; proteomics; disaggregase
资金
- NIH [R01NS083846, R01NS110354, 1R01NS102257]
- Congressionally Directed Medical Research Programs Award [W81XWH-17-1-0564]
- Michael J. Fox Foundation
- Howard Hughes Medical Institute
- Lo Graduate Fellowship for Excellence in Stem Cell Research
- National Institute of Neurological Disorders and Stroke T32 Neurobiology of Cortical Systems [NS007224]
- Interdepartmental Neuroscience Program Grant [T32 NS041228]
- Gruber Foundation
- Yale/National Institute on Drug Abuse Neuroproteomic Center [P30 DA018343]
- National Institutes of Health Shared Instrumentation Grant [S10OD018034]
- Nina Compagnon Hirshfield Parkinson's Disease Research Fund
Parkinson's disease is characterized by the aggregation of the presynaptic protein alpha-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of alpha-synuclein aggregation, molecular facilitators of alpha-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating alpha-synuclein oligomers and fibrils, with a focus on the mammalian disaggregase complex. Here, we show that overexpression of the chaperone Hsp110 is sufficient to reduce alpha-synuclein aggregation in a mammalian cell culture model. Additionally, we demonstrate that Hsp110 effectively mitigates alpha-synuclein pathology in vivo through the characterization of transgenic Hsp110 and double-transgenic alpha-synuclein/Hsp110 mouse models. Unbiased analysis of the synaptic proteome of these mice revealed that overexpression of Hsp110 can override the protein changes driven by the alpha-synuclein transgene. Furthermore, overexpression of Hsp110 is sufficient to prevent endogenous alpha-synuclein templating and spread following injection of aggregated alpha-synuclein seeds into brain, supporting a role for Hsp110 in the prevention and/or disaggregation of alpha-synuclein pathology.
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