ALPHA-SYNUCLEIN TRANSLOCATION TO MITOCHONDRIA ENHANCES FREE RADICAL FORMATION

MARTINEZ J, GALLI S, JARES ERIJMAN EA.

Hotel Casa Serrana, Huerta Grande, Cordoba,

Congreso; I reunión conjunta neurociencias (IRCN),; 2009

Parkinson´s disease (PD) is the second most common neurodegenerative disease, affecting 1% of the population above the age of 65. PD clinical manifestations include Bradykinesia, rest tremor, rigidity and postural instability. The characteristic pathology is the degeneration of dopamine neurons in the substantia nigra and the presence of Lewy bodies which are mainly composed of α-synuclein (AS). Mutations in the AS gene or AS overexpression are causal for familial PD. AS might be damaging to neurons because it is inherently prone to aggregation; mutations or increased concentration of the protein intensify this tendency. Otherwise, small oligomers derived from AS may damage key processes within the cell. Several biochemical abnormalities have been described in the brains of patients with PD, including oxidative stress and mitochondrial dysfunction, although the mechanisms remain unclear. We found ΑS in the mitochondria of rat brain and liver and of HeLa cells. Incubation of ΑS with the isolated organelle caused its entrance into the organelle. Both ΑS monomers and oligomers were found in mitochondria. The incubation of ΑS with mitochondria caused an increase in mitochondrial H2O2, NO and O2- concentration. It was recently described that ΑS regulates mitochondrial NO production by an activation of mtNOS (Parihar et al., Cell. Mol. Life Sci., 2008). An increase in mitochondrial NO may block electron transport chain and increase O2- production by ubisemquinone auto-oxidation, and further H2O by O2- dismutation catalyzed by MnSOD. Therefore, it is plausible that an increase in free radicals may cause modifications on AS and impact oligomer formation, aggregation, and eventually cause cell death.