Abstract
Alpha-synuclein plays an important role in the physiology of cells. However, once aggregated, it can induce pathological changes and lead to Parkinson’s disease. Here we show that two human stem cell derived models with overexpression of alpha-synuclein exhibit dysregulation of calcium signaling, as evidence by abnormal calcium responses to physiological calcium stimuli. This suggests that incorporation of α-synuclein oligomers into the plasma membrane of neurons overexpressing α-synuclein accounts for the aberrant calcium influx in response to physiological stimuli. Prevention of lipid peroxidation by the application of d-PUFAs restores calcium signaling in alpha-synuclein models. We hypothesise that increased levels of alpha-synuclein together with aging in culture results in generation of misfolded proteins, high production of ROS and incorporation of oligomers into membranes, and that this contributes to abnormal signal transduction and mitochondrial dysfunction that leads to pathology. Importantly, ROS production, lipid peroxidation, calcium signal and a-synuclein induced cell death were dependent on the presence of transition metals in the medium and could be prevented by chelators or D-PUFAs.
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