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

2019 | journal article; research paper

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​Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies​
Szegő, É. M.; Dominguez-Meijide, A.; Gerhardt, E.; König, A.; Koss, D. J.; Li, W. & Pinho, R. et al.​ (2019) 
Cell Reports28(1) pp. 65.e6​-77.e6​.​ DOI: https://doi.org/10.1016/j.celrep.2019.06.009 

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Authors
Szegő, Éva M.; Dominguez-Meijide, Antonio; Gerhardt, Ellen; König, Annekatrin; Koss, David J.; Li, Wen; Pinho, Raquel; Fahlbusch, Christiane; Johnson, Mary; Santos, Patricia; Villar-Piqué, Anna; Thom, Tobias; Rizzoli, Silvio ; Schmitz, Matthias; Li, Jiayi; Zerr, Inga; Attems, Johannes; Jahn, Olaf ; Outeiro, Tiago Fleming 
Abstract
Alpha-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.
Issue Date
2019
Journal
Cell Reports 
Project
SFB 1286: Quantitative Synaptologie 
SFB 1286 | B08: Definition von Kaskaden molekularer Veränderungen bei Synucleinopathien während der Neurodegeneration 
Working Group
RG Outeiro (Experimental Neurodegeneration) 
RG Rizzoli (Quantitative Synaptology in Space and Time) 
eISSN
2211-1247
Language
English

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