Oxidative Stress Involvement in α -Synuclein Oligomerization in Parkinson's Disease Cybrids

Abstract

Mitochondrial dysfunction, oxidative stress, and α-synuclein oligomerization occur in Parkinson disease (PD). We used an in vitro PD cybrid approach that models these three phenomena specifically to evaluate the impact of mitochondria-derived oxidative stress on α-synuclein oligomerization. Compared with control cybrid cell lines, reactive oxygen species (ROS) production and protein oxidative stress markers were elevated in PD cybrids. The antioxidants CoQ₁₀ and GSH attenuated changes in PD cybrid peroxide, protein carbonyl, and protein sulfhydryl levels. Elevated PD cybrid α-synuclein oligomer levels were also attenuated by CoQ₁₀ and GSH. In PD cybrids, α-synuclein oligomerization was activated via a complex I–mediated increase in the free tubulin/polymerized tubulin ratio. CoQ₁₀ but not GSH increased complex I activity, restored ATP to control levels, and normalized the PD cybrid free tubulin/polymerized tubulin ratio. Overall, we conclude that two different antioxidants can decrease α-synuclein oligomerization whether by improving mitochondrial function or by preventing protein carbonylation or both. We conclude that mitochondrial dysfunction can induce α-synuclein oligomerization via ATP depletion–driven microtubule depolymerization and via ROS increase–driven protein oxidation.