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Research Article

Hsp110 mitigates α-synuclein pathology in vivo

View ORCID ProfileYumiko V. Taguchi, Erica L. Gorenberg, Maria Nagy, Drake Thrasher, Wayne A. Fenton, Laura Volpicelli-Daley, View ORCID ProfileArthur L. Horwich, and View ORCID ProfileSreeganga S. Chandra
PNAS November 26, 2019 116 (48) 24310-24316; first published November 4, 2019 https://doi.org/10.1073/pnas.1903268116
Yumiko V. Taguchi
aDepartment of Neurology, Yale University, New Haven, CT 06536;
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Erica L. Gorenberg
aDepartment of Neurology, Yale University, New Haven, CT 06536;
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Maria Nagy
bHoward Hughes Medical Institute, Yale University, New Haven, CT 06510;
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Drake Thrasher
cDepartment of Neurology, University of Alabama, Birmingham, AL 35294;
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Wayne A. Fenton
bHoward Hughes Medical Institute, Yale University, New Haven, CT 06510;
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Laura Volpicelli-Daley
cDepartment of Neurology, University of Alabama, Birmingham, AL 35294;
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Arthur L. Horwich
bHoward Hughes Medical Institute, Yale University, New Haven, CT 06510;dDepartment of Genetics, Yale University, New Haven, CT 06510;
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  • ORCID record for Arthur L. Horwich
Sreeganga S. Chandra
aDepartment of Neurology, Yale University, New Haven, CT 06536;eDepartment of Neuroscience, Yale University, New Haven, CT 06536;fYale Stem Cell Center, Yale University, New Haven, CT 06510
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  • ORCID record for Sreeganga S. Chandra
  • For correspondence: sreeganga.chandra@yale.edu
  1. 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.

  • Lewy body
  • chaperone
  • synapse
  • proteomics
  • disaggregase

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
Yumiko V. Taguchi, Erica L. Gorenberg, Maria Nagy, Drake Thrasher, Wayne A. Fenton, Laura Volpicelli-Daley, Arthur L. Horwich, Sreeganga S. Chandra
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24310-24316; DOI: 10.1073/pnas.1903268116

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Hsp110 mitigates α-synuclein pathology in vivo
Yumiko V. Taguchi, Erica L. Gorenberg, Maria Nagy, Drake Thrasher, Wayne A. Fenton, Laura Volpicelli-Daley, Arthur L. Horwich, Sreeganga S. Chandra
Proceedings of the National Academy of Sciences Nov 2019, 116 (48) 24310-24316; DOI: 10.1073/pnas.1903268116
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