The Transgenic Overexpression of α-Synuclein and Not Its Related Pathology Associates with Complex I Inhibition

Virginie Loeb,Eugenia Yakunin,Ann Saada,Ronit Sharon

doi:10.1074/jbc.m109.061051

Virginie Loeb, Eugenia Yakunin + Show 2 more

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https://doi.org/10.1074/jbc.m109.061051

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Abstract

Alpha-synuclein (alphaS) is a protein involved in the cytopathology and genetics of Parkinson disease and is thought to affect mitochondrial complex I activity. Previous studies have shown that mitochondrial toxins and specifically inhibitors of complex I activity enhance alphaS pathogenesis. Here we show that alphaS overexpression specifically inhibits complex I activity in dopaminergic cells and in A53T alphaS transgenic mouse brains. Importantly, our results indicate that the inhibitory effect on complex I activity is not associated with alphaS-related pathology. Specifically, complex I activity measured in purified mitochondria from A53T alphaS transgenic mouse brains was not affected by mouse age; Parkinson disease-like symptoms; levels of alphaS soluble oligomers; levels of insoluble, lipid-associated alphaS; or alphaS intraneuronal depositions in vivo. Likewise, no correlation was found between complex I activity and polyunsaturated fatty acid-induced alphaS depositions in Lewy body-like inclusions in cultured dopaminergic cells. We further show that the effect of alphaS on complex I activity is not due to altered mitochondrial protein levels or affected complex I assembly. Based on the results herein, we suggest that alphaS expression negatively regulates complex I activity as part of its normal, physiological role.

Highlights

␣-Synuclein (␣S) is a presynaptic protein critically involved in the cytopathology and genetics of Parkinson disease (PD)
␣S Overexpression in Cultured Dopaminergic Cells Inhibits Complex I Activity—We initially sought to determine whether ␣S overexpression affects mitochondrial complex I activity in cultured dopaminergic cells
In this study we aimed at assessing whether ␣S pathology, i.e. accumulation of soluble oligomers, insoluble aggregates, or inclusion formation, is directly associated with mitochondrial dysfunction

Summary

Introduction

␣-Synuclein (␣S) is a presynaptic protein critically involved in the cytopathology and genetics of PD (reviewed in Refs. 11–13). Once in the mitochondria, ␣S predominantly associates with the inner mitochondrial membrane, where it can apparently interact with and inhibit complex I activity, resulting in increased reactive oxygen species production [21]. This effect is enhanced by the pathogenic A53T ␣S mutation [21]. We searched for an association between mitochondrial complex I dysfunction and ␣S-related pathology, represented by either ␣S-soluble oligomers, ␣S-insoluble aggregates, PD-like symptoms, or mouse age. We report that ␣S overexpression in cultured dopaminergic cells or A53T ␣S tg mouse brains inhibits complex I activity, yet no correlation between ␣S-related pathology and mitochondrial complex I dysfunction was found. We conclude that ␣S inhibits complex I activity as part of its normal, physiological function

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