Acrolein and Copper as Competitive Effectors of alpha-Synuclein

Mounting evidence supports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by alpha-synuclein (alpha Syn) accumulation and aggregation in brain regions, also promoted by Cu2+. alpha Syn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper, and alpha Syn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on alpha Syn using an approach based on LC-MS/MS analysis. We also evaluated the influence of Cu2+ on the protein carbonylation and how the ACR modification impacts the Cu2+ binding and the production of Reactive Oxygen Species (ROS). Finally, we investigated the effects of ACR and Cu2+ ions on the alpha Syn aggregation by dynamic light scattering and fluorescence assays. Cu2+ regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu2+ and ACR inhibits alpha Syn aggregation both in the presence and in the absence of Cu2+.