Proteomics

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Hsp110 Mitigates α-Synuclein Pathology In Vivo


ABSTRACT: Parkinson’s disease is characterized by the aggregation of the presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of α-synuclein aggregation, molecular facilitators of α-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating α-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 α-synuclein aggregation in a mammalian cell culture model. Additionally, we demonstrate that Hsp110 effectively mitigates α-synuclein pathology in vivo through the characterization of transgenic Hsp110 and double transgenic α-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 α-synuclein transgene. Furthermore, overexpression of Hsp110 is sufficient to prevent endogenous α-synuclein templating and spread following injection of aggregated α-synuclein seeds into brain, supporting a role for Hsp110 in the prevention and/or disaggregation of α-synuclein pathology.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: TuKiet Lam  

LAB HEAD: Sreeganga Chandra

PROVIDER: PXD016015 | Pride | 2020-05-26

REPOSITORIES: Pride

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Hsp110 mitigates α-synuclein pathology in vivo.

Taguchi Yumiko V YV   Gorenberg Erica L EL   Nagy Maria M   Thrasher Drake D   Fenton Wayne A WA   Volpicelli-Daley Laura L   Horwich Arthur L AL   Chandra Sreeganga S SS  

Proceedings of the National Academy of Sciences of the United States of America 20191104 48


Parkinson's disease is characterized by the aggregation of the presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of α-synuclein aggregation, molecular facilitators of α-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating α-synuclein oligomers and fibrils, with a focus on the mammalian disaggregase complex. Here, we show  ...[more]

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