Plasma membrane ion permeability induced by mutant alpha-synuclein contributes to the degeneration of neural cells.
Mutations in alpha-synuclein cause some cases of familial Parkinson's disease (PD), but the mechanism by which alpha-synuclein promotes degeneration of dopamine-producing neurons is unknown. We report that human neural cells expressing mutant alpha-synuclein (A30P and A53T) have higher plasma membrane ion permeability. The higher ion permeability caused by mutant alpha-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 alpha-synuclein. The membrane permeable Ca2+ chelator BAPTA-AM significantly protected the cells against oxidative stress, whereas neither L-type (nifedipine) nor N-type (omega-conotoxin-GVIA) Ca2+ channel blockers protected the cells. These findings suggest that the high membrane ion permeability caused by mutant alpha-synuclein may contribute to the degeneration of neurons in PD.
Furukawa
Katsutoshi
K
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA. tatsfuru@hotmail.com
Matsuzaki-Kobayashi
Michiko
M
Hasegawa
Takafumi
T
Kikuchi
Akio
A
Sugeno
Naoto
N
Itoyama
Yasuto
Y
Wang
Yue
Y
Yao
Pamela J
PJ
Bushlin
Ittai
I
Takeda
Atsushi
A
D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics*; D002614:Chelating Agents / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D002614:Chelating Agents; D051844:alpha-Synuclein; D002118:Calcium; D004298:Dopamine