TOM40 Mediates Mitochondrial Dysfunction Induced by α-Synuclein Accumulation in Parkinson’s Disease

Abstract

Alpha-synuclein (α-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson's disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery--TOM40--might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype α-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in α-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in α-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in α-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in α-Synucleinopathies.

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• Mitochondrial damage by α-synuclein causes cell death in human dopaminergic neurons · 2019
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• Mitochondria in Neuroprotection by Phytochemicals: Bioactive Polyphenols Modulate Mitochondrial Apoptosis System, Function and Structure · 2019
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• Mitochondrial Dysfunction in Parkinson’s Disease—Cause or Consequence? · 2019
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• Mitochondrial Quality Control in Neurodegenerative Diseases: Focus on Parkinson's Disease and Huntington's Disease · 2018
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• Defective mitochondrial protein import contributes to complex I-induced mitochondrial dysfunction and neurodegeneration in Parkinson’s disease · 2018
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• The Close Encounter Between Alpha-Synuclein and Mitochondria · 2018
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• Mitochondrial dynamics in Parkinson's disease: a role for α-synuclein? · 2017
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• Aggregated α-synuclein and complex I deficiency: exploration of their relationship in differentiated neurons · 2015
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