SELECTIVE OXIDATION OF ALPHA-SYNUCLEIN PROMOTES ITS CYTOTOXICITY

FALOMIR LOCKHART, LISANDRO J.; BORSARELLI, CLAUDIO D.; OSTATNÁ, VERONIKA; FAUERBACH, JONATHAN A.; PALECEK, EMIL; JARES ERIJMAN, ELIZABETH A.; JOVIN, THOMAS M.

Huerta Grande

Congreso; XXIX Reunión Anual de la Sociedad Argnetina de Investigación en Neurociencias; 2014

Sociedad Argnetina de Investigación en Neurociencias

Parkinson?s disease is a progressive neurodegenerative disorder, histologically defined by intracellular aggregates of proteins, α-Synuclein (aSyn) mainly, and lipids. Aggregation of aSyn has been associated with selective loss of dopaminergic neurons, in combination with external factors related to lipid and protein oxidation and mitochondrial malfunction. Early intermediates of aSyn aggregates are thought to be the main ?culprits?, rather than mature amyloid fibrils. But a comprehensive description of the relationship between protein aggregation and neuronal death is still missing. We decided to evaluate the effects of aSyn oxidation and formation of crosslinked oligomers. Tunable oxidative modifications of aSyn were achieved using a photo-sensitizer to generate stable covalent oligomers by specific crosslinking of Tyr residues. Different species were isolated and characterized by a complementary set of techniques that demonstrated the presence of diTyrosine crosslinks. This led to reduced aggregation in vitro and increased toxicity towards differentiated SHSY5Y cells. These results suggest that oxidative modifications seem to alter the conformation of aSyn and its tendency to aggregate, possibly stabilizing more toxic species or avoiding its neutralization into amyloid fibers. We anticipate these investigations will assist in the identification of initial molecular triggers leading to neurodegeneration associated with the exposure to ROS promoting compounds.