Modulation of cell death by alpha-synuclein is stimulus-dependent in mammalian cells

alpha-synuclein is a neuronally-expressed protein which is mutated in familial Parkinson's disease. Previous studies have suggested that over-expression of alpha-synuclein can either enhance, reduce or have no effect on the degree of cell death in response to death-inducing stimuli. We resolve this discrepancy by using a well-characterised cell system to demonstrate that wild type alpha-synuclein can enhance cell death in response to ischaemia/reoxygenation or staurosporine treatment whilst protecting against serum removal and dopamine-induced cell death. In contrast, the two mutant forms of alpha-synuclein uniformly enhance cell death. Hence, the disease-associated mutations appear to convert alpha-synuclein from a protein which modulates cell death differently in different circumstances to forms which have a universal damaging effect.