Toggle Main Menu Toggle Search

Open Access padlockePrints

Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies

Lookup NU author(s): Dr David Koss, Mary Johnson, Professor Johannes Attems, Professor Tiago Outeiro

Downloads


Licence

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

© 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.


Publication metadata

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


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share