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Hsp110 mitigates α-synuclein pathology in vivo
Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved October 14, 2019 (received for review February 24, 2019)

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Significance
Recently, the mammalian disaggregase that can disassemble α-synuclein fibrils was reconstituted in vitro. However, it was unclear if this disaggregase can function in vivo. Here we show that overexpressing Hsp110, a limiting component of the disaggregase, is beneficial in reducing α-synuclein fibrillar pathology in 2 distinct mouse models of Parkinson’s disease. This reduction in α-synuclein pathology leads to improved survival. Significantly, Hsp110 overexpression is associated with a broad elevation of chaperones and may be an effective therapeutic strategy against synucleinopathies.
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: sreeganga.chandra{at}yale.edu.
Author contributions: Y.V.T., W.A.F., L.V.-D., A.L.H., and S.S.C. designed research; Y.V.T., E.L.G., M.N., D.T., and L.V.-D. performed research; Y.V.T., E.L.G., L.V.-D., A.L.H., and S.S.C. analyzed data; and Y.V.T., E.L.G., W.A.F., L.V.-D., A.L.H., and S.S.C. wrote the paper.
The authors declare no competing interest.
This article is a PNAS Direct Submission.
Data deposition: The data reported in this article have been deposited in the PRIDE database, https://www.ebi.ac.uk/pride/archive/ (accession no. PXD016015).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1903268116/-/DCSupplemental.
Published under the PNAS license.
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