Mutations in α-synuclein cause some cases of familial Parkinson's disease (PD), but the mechanism by which α-synuclein promotes degeneration of dopamine-producing neurons is unknown. We report that human neural cells expressing mutant α-synuclein (A30P and A53T) have higher plasma membrane ion permeability. The higher ion permeability caused by mutant α-synuclein would be because of relatively large pores through which most cations can pass non-selectively. Both the basal level of [Ca2+]i and the Ca2+ response to membrane depolarization are greater in cells expressing mutant α-synuclein. The membrane permeable Ca2+ chelator BAPTA-AM significantly protected the cells against oxidative stress, whereas neither l-type (nifedipine) nor N-type (ω-conotoxin-GVIA) Ca2+ channel blockers protected the cells. These findings suggest that the high membrane ion permeability caused by mutant α-synuclein may contribute to the degeneration of neurons in PD.