alpha-Synuclein implicated in Parkinson's disease catalyses the formation of hydrogen peroxide in vitro

Some rare inherited forms of Parkinson's disease (PD) are due to mutations in the gene encoding a 140-amino acid presynaptic protein called alpha -syn uclein. In PD, and some other related disorders such as dementia with Lewy bodies, alpha -synuclein accumulates in the brain in the form of fibrillar aggregates, which are found inside the neuronal cytoplasmic inclusions know n as Lewy bodies. By means of an electron spin resonance (ESR) spin trappin g method, we show here that solutions of full-length alpha -synuclein, and a synthetic peptide fragment of alpha -synuclein corresponding to residues 61-95 (the so-called non-A beta component or NAC), both liberate hydroxyl r adicals upon incubation in vitro followed by the addition of Fe(II). We did not observe this property for the related beta- and gamma -synucleins, whi ch are not found in Lewy bodies, and are not linked genetically to any neur odegenerative disorder. There is abundant evidence for the involvement of f ree radicals and oxidative stress in the pathogenesis of nigral damage in P D. Our new data suggest that the fundamental molecular mechanism underlying this pathological process could be the production of hydrogen peroxide by alpha -synuclein. (C) 2001 Elsevier Science Inc.