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