Cytosolic Trapping of a Mitochondrial Heat Shock Protein Is an Early Pathological Event in Synucleinopathies
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
Affiliations
Éva M. Szegő
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany; Corresponding author
Antonio Dominguez-Meijide
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Ellen Gerhardt
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Annekatrin König
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
David J. Koss
Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Wen Li
Institute of Heath Sciences, China Medical University, 110112 Shenyang, P. R. China; Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, BMC A10, 221 84 Lund, Sweden
Raquel Pinho
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Christiane Fahlbusch
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Mary Johnson
Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Patricia Santos
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Anna Villar-Piqué
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany
Tobias Thom
Department of Neurology, University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Robert-Koch Street 40, Göttingen 37075, Germany
Silvio Rizzoli
Department of Neuro- and Sensory Physiology, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Humboldtallee 23, Göttingen 37073, Germany
Matthias Schmitz
Department of Neurology, University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Robert-Koch Street 40, Göttingen 37075, Germany
Jiayi Li
Institute of Heath Sciences, China Medical University, 110112 Shenyang, P. R. China; Neural Plasticity and Repair Unit, Wallenberg Neuroscience Center, Department of Experimental Medical Science, BMC A10, 221 84 Lund, Sweden
Inga Zerr
Department of Neurology, University Medical Center and German Center for Neurodegenerative Diseases (DZNE), Robert-Koch Street 40, Göttingen 37075, Germany
Johannes Attems
Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
Olaf Jahn
Proteomics Group, Max Planck Institute of Experimental Medicine, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, Hermann Rein Street 3, Göttingen 37075, Germany
Tiago F. Outeiro
Department of Experimental Neurodegeneration, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center, Waldweg 33, Göttingen 37073, Germany; Institute of Neuroscience, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne NE2 4HH, UK; Max Planck Institute of Experimental Medicine, Hermann Rein Street 3, Göttingen 37075, Germany; Corresponding author
Summary: 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. Keywords: HSP10, alpha-synuclein, Parkinson’s disease, mitochondria, synaptosome, striatum, proteostasis
