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

• DOI: 10.1016/j.celrep.2019.06.009
• Publication Date: 2019-07-02T14:39:00Z
• Authors: Éva M. Szegő; Antonio Dominguez...; Ellen Gerhardt; Annekatrin König; David J. Koss; Wen Li; Raquel Pinho; Christiane Fahlbusch; Mary Johnson; Patricia Santos; Anna Villar-Piqué; Tobias Thom; Silvio Rizzoli; Matthias Schmitz; Jiayi Li; Inga Zerr; Johannes Attems; Olaf Jahn; Tiago F. Outeiro
• Keywords: Synucleinopathies; HSP60; Proteostasis

Alpha-synuclein (aSyn) accumulates in intracellular inclusions synucleinopathies, but the molecular mechanisms leading to disease are unclear. We identify 10 kDa heat shock protein (HSP10) as a mediator of aSyn-induced mitochondrial impairments striatal synaptosomes. find an age-associated increase cytosolic levels HSP10, and concomitant decrease levels, aSyn transgenic mice. The superoxide dismutase 2, client HSP10/HSP60 folding complex, synaptosomal spare respiratory capacity also reduced. Overexpression HSP10 ameliorates aSyn-associated dysfunction delays pathology vitro vivo. Altogether, our data indicate that increased induce deficits, at least partially, by sequestering cytosol preventing it from acting mitochondria. Importantly, these alterations manifest first presynaptic terminals. Our study not only provides mechanistic insight into synucleinopathies opens new avenues for targeting underlying cellular pathologies.