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Lookup NU author(s): Dr David KossORCiD, Mary Johnson, Professor Johannes Attems, Professor Tiago OuteiroORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2019 The AuthorsAlpha-synuclein (aSyn) accumulates in intracellular inclusions in synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify the 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments in striatal synaptosomes. We find an age-associated increase in the cytosolic levels of HSP10, and a concomitant decrease in the mitochondrial levels, in aSyn transgenic mice. The levels of superoxide dismutase 2, a client of the HSP10/HSP60 folding complex, and synaptosomal spare respiratory capacity are also reduced. Overexpression of HSP10 ameliorates aSyn-associated mitochondrial dysfunction and delays aSyn pathology in vitro and in vivo. Altogether, our data indicate that increased levels of aSyn induce mitochondrial deficits, at least partially, by sequestering HSP10 in the cytosol and preventing it from acting in mitochondria. Importantly, these alterations manifest first at presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies but opens new avenues for targeting underlying cellular pathologies. Szegő et al. identify HSP10 as a modulator of alpha-synuclein-induced mitochondrial impairment in striatal synaptosomes. Age-associated increase in the cytosolic and decrease in mitochondrial levels of HSP10 results in a reduction in the levels of SOD2 and of synaptosomal ATP production on demand. HSP10 overexpression delays alpha-synuclein pathology both in vitro and in vivo.
Author(s): Szego EM, Dominguez-Meijide A, Gerhardt E, Konig A, Koss DJ, Li W, Pinho R, Fahlbusch C, Johnson M, Santos P, Villar-Pique A, Thom T, Rizzoli S, Schmitz M, Li J, Zerr I, Attems J, Jahn O, Outeiro TF
Publication type: Article
Publication status: Published
Journal: Cell Reports
Year: 2019
Volume: 28
Issue: 1
Pages: 65-77.e6
Print publication date: 02/07/2019
Online publication date: 02/07/2019
Acceptance date: 03/06/2019
Date deposited: 09/07/2019
ISSN (electronic): 2211-1247
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.celrep.2019.06.009
DOI: 10.1016/j.celrep.2019.06.009
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