Deregulation of calcium homeostasis mediates secreted α–synuclein-induced neurotoxicity

Abstract α-Synuclein (AS) plays a crucial role in Parkinson's disease pathogenesis. AS is normally secreted from neuronal cells and can thus exert paracrine effects. We have previously demonstrated that naturally secreted AS species, derived from SH-SY5Y cells inducibly overexpressing human wild type AS, can be toxic to recipient neuronal cells. In the current study, we show that application of secreted AS alters membrane fluidity and increases calcium (Ca 2+ ) entry. This influx is reduced on pharmacological inhibition of voltage-operated Ca 2+ channels. Although no change in free cytosolic Ca 2+ levels is observed, a significantly increased mitochondrial Ca 2+ sequestration is found in recipient cells. Application of voltage-operated Ca 2+ channel blockers or Ca 2+ chelators abolishes AS-mediated toxicity. AS-treated cells exhibit increased calpain activation, and calpain inhibition greatly alleviates the observed toxicity. Collectively, our data suggest that secreted AS exerts toxicity through engagement, at least in part, of the Ca 2+ homeostatic machinery. Therefore, manipulating Ca 2+ signaling pathways might represent a potential therapeutic strategy for Parkinson's disease.