Oxidative modification of alpha-Synuclein modifies its cytotoxicity

FALOMIR LOCKHART LJ; BORSARELLI CD; OSTATNÁ V; FAUERBACH JA; PALECEK E; JARES ERIJMAN EA; JOVIN TM

San Diego

Congreso; 56th BPS Meeting - San Diego; 2012

BPS - UCSD

Parkinson’s disease is a progressive neurodegenerative disorder, histologically defined by intracellular aggregates of proteins and lipids, associated with selective loss of dopaminergic neurons. The protein alpha-Synuclein (aSyn) is the most abundant component in these aggregates and has been identified as a key player in a series of neurodegenerative diseases. Early intermediates are thought to be the main “culprits”, in combination with oxidative stress and lipid oxidation. Nevertheless, a comprehensive description of the relationship between protein aggregation and selective neuronal death is still missing. Photo-tunable oxidative modifications of aSyn were achieved using a sensitizer-dependent radical mechanism to generate stable covalent oligomers by specific crosslinking of Tyr residues. Different species were isolated and characterized by a complementary set of techniques, such as spectroscopy, electrochemistry and biochemical characterization that demonstrated the presence of diTyrosine crosslinkings. This led to reduced aggregation in vitro, possibly stabilizing more toxic species or avoiding its neutralization into amyloid fibers. Furthermore, modified covalent oligomer showed increased toxicity upon exposure of differentiated SH-SY5Y cells.