Research ArticleParkinson’s Disease

α-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson’s disease

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Science Translational Medicine  08 Jun 2016:
Vol. 8, Issue 342, pp. 342ra78
DOI: 10.1126/scitranslmed.aaf3634

α-Synuclein disrupts the mitochondrial protein import business

α-Synuclein accumulation and mitochondrial dysfunction are central to the pathogenesis of most forms of Parkinson’s disease and appear to intersect, but how the two are related to each other has remained elusive. Now, Di Maio and colleagues report that specific forms of wild-type α-synuclein, such as oligomeric and dopamine-modified forms, but not the monomeric or fibrillar forms, bind with high affinity to the mitochondrial receptor TOM20. This results in impaired import of proteins required for mitochondrial function and leads to senescence of mitochondria, which show reduced respiration and increased production of reactive oxygen species. This study also highlights potential ways to prevent this deleterious interaction and its downstream consequences.


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.

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