Furukawa Katsutoshi, Matsuzaki-Kobayashi Michiko, Hasegawa Takafumi, Kikuchi Akio, Sugeno Naoto, Itoyama Yasuto, Wang Yue, Yao Pamela J, Bushlin Ittai, Takeda Atsushi
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.
J Neurochem. 2006 May;97(4):1071-7. doi: 10.1111/j.1471-4159.2006.03803.x. Epub 2006 Apr 5.
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.
α-突触核蛋白的突变会导致一些家族性帕金森病（PD）病例，但α-突触核蛋白促进多巴胺能神经元变性的机制尚不清楚。我们报告称，表达突变型α-突触核蛋白（A30P和A53T）的人类神经细胞具有更高的质膜离子通透性。突变型α-突触核蛋白引起的更高离子通透性是由于存在相对较大的孔，大多数阳离子可通过这些孔进行非选择性通透。在表达突变型α-突触核蛋白的细胞中，[Ca2+]i的基础水平以及对膜去极化的Ca2+反应均更强。膜通透性Ca2+螯合剂BAPTA-AM可显著保护细胞免受氧化应激，而L型（硝苯地平）和N型（ω-芋螺毒素-GVIA）Ca2+通道阻滞剂均不能保护细胞。这些发现表明，突变型α-突触核蛋白引起的高膜离子通透性可能导致PD中神经元的变性。
