α-Synuclein promotes clathrin-mediated NMDA receptor endocytosis and attenuates NMDA-induced dopaminergic cell death

被引：70

作者：

Cheng, Furong ^{[2
]}

Li, Xin ^{[2
]}

Li, Yaohua ^{[2
]}

Wang, Chaodong ^{[2
]}

Wang, Tao ^{[2
]}

Liu, Guangwei ^{[2
]}

Baskys, Andrius ^{[3
]}

Ueda, Kenji ^{[2
,4
]}

Chan, Piu ^{[2
]}

Yu, Shun ^{[1
,2
]}

机构：

[1] China Capital Med Univ, Xuanwu Hosp, Beijing Inst Geriatr, Dept Neurobiol, Beijing 100053, Peoples R China

[2] China Capital Med Univ, Xuanwu Hosp, Key Lab Neurodegenerat Dis,Capital Med Univ, Sino Japan Joint Lab Neurodegenerat Dis,Minst Edu, Beijing 100053, Peoples R China

[3] Univ Calif Los Angeles, David Geffen Sch Med, UCLA Kern Psychiat Residency Program, Kern Med Ctr & Kern Cty Mental Hlth, Bakersfield, CA USA

[4] Tokyo Inst Psychiat, Div Psychobiol, Tokyo, Japan

来源：

JOURNAL OF NEUROCHEMISTRY | 2011年 / 119卷 / 04期

基金：

中国国家自然科学基金;

关键词：

alpha-synuclein; cytotoxicity; endocytosis; NMDA; RAB5B; PARKINSONS-DISEASE; GLUTAMATE RECEPTORS; LEWY BODIES; FATTY-ACIDS; DEMENTIA; MUTATION; BRAIN; LOCALIZATION; ACTIVATION; PATHWAYS;

D O I：

10.1111/j.1471-4159.2011.07460.x

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Abnormalities of alpha-synuclein (alpha-syn) and NMDA receptors (NMDARs) are implicated in the pathogenesis of Parkinson's disease. However, how these proteins interact with each other has not been elucidated. Here, the effect of alpha-syn on NMDARs was investigated by examining the alterations of surface NMDAR NR1 subunits in MES23.5 dopaminergic cells transfected with the human alpha-syn gene as well as in cells treated with extracellularly added human alpha-syn. As demonstrated previously that alpha-syn can enter cells in a non-endocytic manner without being degraded by the cellular proteolytic systems, the extracellularly added alpha-syn entered the cytoplasm of MES23.5 cells in a concentration-dependent manner. Both the alpha-syn-transfected cells and alpha-syn-treated cells exhibited increased intracellular alpha-syn levels and reduced surface NR1 without altering the total NR1. The alpha-syn-induced surface NR1 reduction was accompanied by suppression of NMDA-elicited intracellular Ca2+ elevation and reductions of NMDA-induced caspase 3 activation and cell death, which was abolished by hypotonic shock and K+ depletion, a procedure that blocks clathrin-mediated endocytosis, and by suppression of RAB5B expression with anti-RAB5B oligonucleotides. The data obtained provide evidence for the first time that alpha-syn may promote clathrin-mediated NMDAR endocytosis.

引用

页码：815 / 825

页数：11

共 56 条

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