Calcium is a key factor in α-synuclein induced neurotoxicity

Abstract

Aggregation of α-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 α-synuclein on calcium signalling in primary neurons and astrocytes using live neuronal imaging and electrophysiology on artificial membranes. We demonstrate that α-synuclein induces an increase in basal intracellular calcium in its unfolded monomeric state as well as in its oligomeric state. Electrophysiology of artificial membranes demonstrated that α-synuclein monomers induce irregular ionic currents, while α-synuclein oligomers induce rare discrete channel formation. Despite the ability for monomeric α-synuclein to affect calcium signalling, it is only the oligomeric form of α-synuclein that induces cell death. Oligomer-induced cell death was abolished by the exclusion of extracellular calcium, which prevented the α-synuclein induced calcium dysregulation. The findings of this study confirm that α-synuclein interacts with membranes to affect calcium signalling in a structure-specific manner and the oligomeric beta sheet rich α-synuclein species ultimately leads to calcium dysregulation and calcium dependent cell death.