Extracellular high molecular weight α-synuclein oligomers induce cell death by disrupting the plasma membrane

alpha-Synuclein (alpha S), the causative protein of Parkinson's disease and other alpha-synucleinopathies, aggregates from a low molecular weight form (LMW-alpha S) to a high molecular weight alpha S oligomer (HMW-alpha So). Aggregated alpha S accumulates intracellularly, induces intrinsic apoptosis, is released extracellularly, and appears to propagate disease through prion-like spreading. Whether extracellular alpha S aggregates are cytotoxic, damage cell wall, or induce cell death is unclear. We investigated cytotoxicity and cell death caused by HMW-alpha So or LMW-alpha S. Extracellular HMW-alpha So was more cytotoxic than LMW-alpha S and was a crucial factor for inducing plasma membrane damage and cell death. HMW-alpha So induced reactive oxygen species production and phospholipid peroxidation in the membrane, thereby impairing calcium homeostasis and disrupting plasma membrane integrity. HMW-alpha So also induced extrinsic apoptosis and cell death by activating acidic sphingomyelinase. Thus, as extracellular HMW-alpha So causes neuronal injury and death via cellular transmission and direct plasma membrane damage, we propose an additional disease progression pathway for alpha-synucleinopathies.