α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease.
α-Synuclein accumulation and mitochondrial dysfunction have both been strongly implicated in the pathogenesis of Parkinson's disease (PD), and the two appear to be related. Mitochondrial dysfunction leads to accumulation and oligomerization of α-synuclein, and increased levels of α-synuclein cause mitochondrial impairment, but the basis for this bidirectional interaction remains obscure. We now report that certain posttranslationally modified species of α-synuclein bind with high affinity to the TOM20 (translocase of the outer membrane 20) presequence receptor of the mitochondrial protein import machinery. This binding prevented the interaction of TOM20 with its co-receptor, TOM22, and impaired mitochondrial protein import. Consequently, there were deficient mitochondrial respiration, enhanced production of reactive oxygen species, and loss of mitochondrial membrane potential. Examination of postmortem brain tissue from PD patients revealed an aberrant α-synuclein-TOM20 interaction in nigrostriatal dopaminergic neurons that was associated with loss of imported mitochondrial proteins, thereby confirming this pathogenic process in the human disease. Modest knockdown of endogenous α-synuclein was sufficient to maintain mitochondrial protein import in an in vivo model of PD. Furthermore, in in vitro systems, overexpression of TOM20 or a mitochondrial targeting signal peptide had beneficial effects and preserved mitochondrial protein import. This study characterizes a pathogenic mechanism in PD, identifies toxic species of wild-type α-synuclein, and reveals potential new therapeutic strategies for neuroprotection.
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Ri.MED Foundation, Palermo, Italy.
Roberto
R
Di Maio
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Paul J
PJ
Barrett
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Eric K
EK
Hoffman
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Caitlyn W
CW
Barrett
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Alevtina
A
Zharikov
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Life Science and Bioinformatics, Assam University, Silchar 788011, India.
Anupom
A
Borah
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Xiaoping
X
Hu
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Jennifer
J
McCoy
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Charleen T
CT
Chu
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA.
Edward A
EA
Burton
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
Teresa G
TG
Hastings
Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, PA 15213, USA. Department of Neurology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Geriatric Research Education and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA 15240, USA. jgreena@pitt.edu.
J Timothy
JT
Greenamyre
D000818:Animals; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport / Q000235:genetics / Q000502:physiology; D051381:Rats; D011922:Rats, Mutant Strains; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D024101:Mitochondrial Proteins; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; C489998:Tomm20 protein, rat; D051844:alpha-Synuclein