Mutations in parkin are implicated in the pathogenesis of autosomal recessive juvenile parkinsonism (AR-JP) disease. We show that homozygote Cys212Tyr parkin mutation in AR-JP patients renders lymphocytes sensitive to dopamine, iron and hydrogen peroxide stimuli. Indeed, dopamine-induced apoptosis by four alternative mechanisms converging on caspase-3 activation and apoptotic morphology: (1) NF-kappaB-dependent pathway; mitochondrial dysfunction either by (2) H(2)O(2) or (3) hydroxyl exposure and (4) increase of unfolded-protein stress. We also demonstrate that 17beta-estradiol and testosterone prevent homozygote lymphocytes from oxidative stressors-evoked apoptosis. These results may contribute to understanding the relationship between genetic and environmental factors and iron in AR-JP.
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