Study of Selective Tyrosine Oxidation and Nitration Dependence on á-Synuclein Conformational Changes

EZEQUIEL GIMENEZ; ANDRES MARTIN TOSCANI; ANTONELLA LEON; MARIA ALEJANDRA CARRERO RIVERO; GIAN FRANCO CAVAZZUTTI; BETINA CORSICO; LISANDRO J. FALOMIR LOCKHART

Odense

Otro; EMBO Practical Course ?Characterization of post-translational modifications in cellular signaling?; 2017

Deparment of Biochemistry and Molecular Biology, University of Southern Denmark

Parkinson s Disease (PD) is a progressive neurodegenerative condition present in more than 1% of the population older than 60 years. The clinical picture is characterized by motor symptoms, memory loss, reduction or loss of sense of smell and sleep disorders that mostly arise after selective loss of dopaminergic neurons. Synucleopathies, like PD, are histologically defined by amyloid aggregates of proteins and lipids, such as Lewy Bodies, of which a-Synuclein (aSyn) is the most abundant component. Unfortunately, a comprehensive description that explains the relationship between the amyloid aggregates and selective cell death is still to be achieved, especially because the cellular toxic species have not yet been identified. In this regard, several aSyn s PTMs have been identified such as phosphorylation, acetylation, ubiquitylation and SUMOylation, as well as some oxidative modifications. Although a precise correlation between the mentioned aSyn modification and PD has not been established, new data point towards, not only the early aggregates(oligomers and supramolecular intermediates), but also to oxidative modifications of aSyn as the main ?gculprits?h in PD aetiology and dissemination [1,2].An underlying oxidative process, linked also to mitochondrial functionality, is undoubtedly involved. The normal functions of aSyn are still unknown, probably associated to vesicle traffic or its regulation. Particularly, aSyn has the capacity to adopt multiple conformations in response to different interacting partners (that may stabilize or disrupt its normal functions), as well as to oxidative modifications. In this regard, diTyr covalent crosslinking and Tyr-residue nitration, could trigger or enhance the toxic effects of aSyn, leading to the progression of the disease. Previous results showed that diTyr-dependent covalent oligomerization of ?¿Syn may be blocking neutralization of toxic species into inert amyloid fibrils and, therefore, enhancing their cytotoxicity. A better understanding of the role of oxidative modifications in the early stages of PD could lead to the identification of putative new strategies for early diagnosis and therapeutic targets.