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

Research output: Contribution to journalArticle

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. 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.

Details

Authors
  • Éva M. Szegő
  • Antonio Dominguez-Meijide
  • 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
Organisations
External organisations
  • University Medical Center Göttingen
  • University of Newcastle upon Tyne
  • China Medical University, Shenyang
  • German Center for Neurodegenerative Diseases (DZNE), Bonn
  • Max Planck Institute of Experimental Medicine
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology

Keywords

  • alpha-synuclein, HSP10, mitochondria, Parkinson's disease, proteostasis, striatum, synaptosome
Original languageEnglish
Pages (from-to)65-77.e6
JournalCell Reports
Volume28
Issue number1
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes