Oxidative Stress involvement in alpha-synuclein oligomerization in Parkinsons disease cybrids.

Coimbra, Portugal; esteves.raquel@gmail.com.

Mitochondrial dysfunction, oxidative stress, and alpha-synuclein oligomerization occur in Parkinsons disease (PD). We used an in vitro PD cybrid approach that models these three phenomena to specifically evaluate the impact of mitochondria-derived oxidative stress on alpha-synuclein oligomerization. Compared to 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 alpha-synuclein oligomer levels were also attenuated by CoQ10 and GSH. In PD cybrids alpha-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 alpha-synuclein oligomerization whether by improving mitochondrial function and/or by preventing protein carbonylation. Taken together we conclude that mitochondrial dysfunction can induce alpha-synuclein oligomerization via ATP depletion-driven microtubule depolymerization and via ROS increase-driven protein oxidation.

PMID: 18717628 [PubMed - as supplied by publisher]