Oxidative stress involvement in alpha-synuclein oligomerization in Parkinson's disease cybrids.
Mitochondrial dysfunction, oxidative stress, and alpha-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 alpha-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 CoQ(10) and GSH attenuated changes in PD cybrid peroxide, protein carbonyl, and protein sulfhydryl levels. Elevated PD cybrid alpha-synuclein oligomer levels were also attenuated by CoQ(10) and GSH. In PD cybrids, alpha-synuclein oligomerization was activated via a complex I-mediated increase in the free tubulin/polymerized tubulin ratio. CoQ(10) 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 alpha-synuclein oligomerization whether by improving mitochondrial function or by preventing protein carbonylation or both. We conclude that mitochondrial dysfunction can induce alpha-synuclein oligomerization via ATP depletion-driven microtubule depolymerization and via ROS increase-driven protein oxidation.
Esteves
A Raquel
AR
Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
Arduíno
Daniela M
DM
Swerdlow
Russell H
RH
Oliveira
Catarina R
CR
Cardoso
Sandra M
SM
D001704:Biopolymers / Q000378:metabolism*; D015153:Blotting, Western; D004591:Electrophoresis, Polyacrylamide Gel; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D001704:Biopolymers; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D014451:Ubiquinone; C024989:coenzyme Q10; D005978:Glutathione