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

Abstract

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 post-translationally modified species of α-synuclein bind with high-affinity to the TOM20 presequence receptor of the mitochondrial protein import machinery, prevent its interaction with its co-receptor, TOM22, and impair mitochondrial protein import. As a consequence, there is deficient mitochondrial respiration, enhanced ROS production and loss of mitochondrial membrane potential. Examination of postmortem PD tissue reveals an aberrant α-synuclein:TOM20 interaction in nigrostriatal neurons that is associated with loss of imported mitochondrial protein, 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 protein import. This study defines a new pathogenic mechanism in PD, identifies toxic species of wildtype α-synuclein, and reveals new therapeutic strategies for neuroprotection.

Mitochondrial division inhibitor-1 is neuroprotective in the A53T-α-synuclein rat model of Parkinson’s disease

“…demonstrated that mice with global overexpression of human wild type α-syn in the brain using the Thy1 promoter exhibited age dependent accumulation of α-syn in mitochondria in the nigrostriatal dopaminergic pathway, impaired electron transport chain function and enhanced oxidative stress 42 . Recently, Greenamyre’s laboratory reported that specific forms of post-translationally modified α-syn bind with high affinity to the mitochondrial receptor TOM20, resulting in mitochondrial dysfunction and production of reactive oxygen species 45 . From the Zhuang’s group, inducible hA53T-α-syn mice exhibited severe mitochondrial fragmentation that preceded dopaminergic neurodegeneration and other pathologies 19 .…”

Superoxide is the critical driver of DOPAL autoxidation, lysyl adduct formation, and crosslinking of α-synuclein

“…Recently, it was reported that certain post-translationally-modified forms of α-synuclein – including small, covalent oligomers – can bind to and disrupt the mitochondrial protein import machinery, causing impaired respiration and inducing oxidative stress [33]. Such a pathway highlights the fact that DOPAL-mediated α-synuclein oligomers could both initiate PD mechanisms and result from them.…”

Proteinopathy, oxidative stress and mitochondrial dysfunction: cross talk in Alzheimer's disease and Parkinson's disease

“…In experimental models of PD, enhanced production of ROS has been observed, with alterations of the antioxidant enzyme levels 144. Mitochondrial dysfunction caused by α-synuclein could be a source of enhanced production of ROS, as has been observed in several experimental models 140,145. Overexpression of wild or mutant α-synuclein in SH-SY5Y cells has also been shown to increase the intracellular level of ROS 146.…”