Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein.
alpha-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 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.
Zhang
Wei
W
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA.
Dallas
Shannon
S
Zhang
Dan
D
Guo
Jian-Ping
JP
Pang
Hao
H
Wilson
Belinda
B
Miller
David S
DS
Chen
Biao
B
Zhang
Wanqin
W
McGeer
Patrick L
PL
Hong
Jau-Shyong
JS
Zhang
Jing
J
D000818:Animals; D002478:Cells, Cultured; D004298:Dopamine / Q000502:physiology*; D007150:Immunohistochemistry; D016177:Macrophage-1 Antigen / Q000502:physiology*; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism*; D009154:Mutation / Q000502:physiology; D019255:NADPH Oxidases / Q000502:physiology*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000503:physiopathology*; D020258:Neurotoxicity Syndromes / Q000503:physiopathology; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D017382:Reactive Oxygen Species / Q000378:metabolism; D051843:Synucleins / Q000235:genetics* / Q000633:toxicity*
D016177:Macrophage-1 Antigen; D017382:Reactive Oxygen Species; D051843:Synucleins; D019255:NADPH Oxidases; D004298:Dopamine