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Microglial PHOX and Mac‐1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha‐synuclein
Author(s) -
Zhang Wei,
Dallas Shan,
Zhang Dan,
Guo JianPing,
Pang Hao,
Wilson Belinda,
Miller David S.,
Chen Biao,
Zhang Wanqin,
McGeer Patrick L.,
Hong JauShyong,
Zhang Jing
Publication year - 2007
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.20532
Subject(s) - neurodegeneration , alpha synuclein , neurotoxicity , microglia , biology , dopaminergic , microbiology and biotechnology , parkinson's disease , neuroscience , dopamine , medicine , immunology , disease , toxicity , inflammation
α‐Synuclein, a gene whose mutations, duplication, and triplication 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 α‐synuclein has been attributed to date largely to faster formation of α‐synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) α‐synuclein‐elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated α‐synuclein could activate microglia more powerfully than WT α‐synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that α‐synuclein with the A30P or A53T mutations caused greater microglial activation than WT α‐synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant α‐synuclein. Mutant α‐synuclein also induced greater production of reactive oxygen species than WT α‐synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen‐1 (Mac‐1) receptor, rather than α‐synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant α‐synuclein. © 2007 Wiley‐Liss, Inc.