Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein

被引:129
作者
Zhang, Wei
Dallas, Shannon
Zhang, Dan
Guo, Juan-Ping
Pang, Hao
Wilson, Belinda
Miller, David S.
Chen, Biao
Zhang, Wanqin
McGeer, Patrick L.
Hong, Jau-Shyong
Zhang, Jing
机构
[1] Univ Washington, Harborview Med Ctr, Sch Med, Div Neuropathol,Dept Pathol, Seattle, WA 98104 USA
[2] Dalian Med Univ, Dept Physiol, Dalian, Peoples R China
[3] Capital Univ Med Sci, Xuanwu Hosp, Dept Neurol, Beijing, Peoples R China
[4] NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA
[5] Capital Med Univ, Beijign Tian Tan Hosp, Dept Neurol, Beijing, Peoples R China
[6] NIEHS, Intracellular Regulat Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA
[7] Univ British Columbia, Kinsmen Lab Neurol Res, Vancouver, BC V5Z 1M9, Canada
关键词
Parkinson's disease; microglia; synuclein;
D O I
10.1002/glia.20532
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
alpha-Synuclein, a gene whose mutations, duplication, and trip lication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein. (C) 2007 Wiley-Liss, Inc.
引用
收藏
页码:1178 / 1188
页数:11
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