Plasma membrane ion permeability induced by mutant α-synuclein contributes to the degeneration of neural cells

Authors


Address correspondence and reprint requests to Katsutoshi Furukawa MD PhD at his present address, which is the Department of Geriatric and Complementary Medicine, Tohoku University School of Medicine, 2–1 Seiryo-cho, Aobaku, Sendai, Japan. E-mail: katsfuru@hotmail.com

Abstract

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.

Ancillary