Cellular prion protein and calcium ions trigger the neurotoxicity of α-synuclein aggregates

α-Synuclein (αS) aggregation and deposition are associated with the onset and progression of Parkinson’s disease (PD) and other synucleinopathies. Here, we explored the role of the cellular prion protein (PrP ^C ) in the cytotoxic cascade induced by αS prefibrillar oligomers and fibrils in human iPSC-derived dopaminergic neurons, primary rat cortical neurons and human neuroblastoma cells. Using high resolution confocal microscopy and both siRNA-mediated PrP ^C silencing and blockade with an anti-PrP ^C antibody, we showed that PrP ^C mediates the rapid recruitment of αS aggregates at the plasma membrane, resulting in massive Ca ²⁺ influx and membrane permeabilisation, with only a minor contribution to the release of toxic oligomers from aS fibrils and the downstream events leading to cell death. aS aggregates neurotoxicity was largely associated with the presence of extracellular Ca ²⁺ , that directly promoted the cell membrane recruitment and penetration of αS oligomers inside neurons, allowing them to cause neuronal death after prolonged times of exposure with the cells.