Ca2+ is a key factor in α-synuclein-induced neurotoxicity

Aggregation of alpha-synuclein leads to the formation of oligomeric intermediates that can interact with membranes to form pores. However, it is unknown how this leads to cell toxicity in Parkinson's disease. We investigated the species-specific effects of alpha-synuclein on Ca2+ signalling in primary neurons and astrocytes using live neuronal imaging and electrophysiology on artificial membranes. We demonstrate that alpha-synuclein induces an increase in basal intracellular Ca2+ in its unfolded monomeric state as well as in its oligomeric state. Electrophysiology of artificial membranes demonstrated that alpha-synuclein monomers induce irregular ionic currents, whereas alpha-synuclein oligomers induce rare discrete channel formation events. Despite the ability of monomeric alpha-synuclein to affect Ca2+ signalling, it is only the oligomeric form of alpha-synuclein that induces cell death. Oligomer-induced cell death was abolished by the exclusion of extracellular Ca2+, which prevented the alpha-synuclein-induced Ca2+ dysregulation. The findings of this study confirm that alpha-synuclein interacts with membranes to affect Ca2+ signalling in a structure-specific manner and the oligomeric beta-sheet-rich alpha-synuclein species ultimately leads to Ca2+ dysregulation and Ca2+-dependent cell death.