Zhang Wei, Dallas Shannon, Zhang Dan, Guo Jian-Ping, Pang Hao, Wilson Belinda, Miller David S, Chen Biao, Zhang Wanqin, McGeer Patrick L, Hong Jau-Shyong, Zhang Jing
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina, USA.
Glia. 2007 Aug 15;55(11):1178-88. doi: 10.1002/glia.20532.
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.
α-突触核蛋白，一种其突变、重复和三倍体与常染色体显性家族性帕金森病（fPD）相关的基因，似乎在散发性帕金森病（sPD）的发病机制中也起着核心作用。迄今为止，突变型α-突触核蛋白诱导的神经退行性变增强主要归因于神经元中α-突触核蛋白聚集体的更快形成。最近，我们报道小胶质细胞激活增强野生型（WT）α-突触核蛋白引发的多巴胺能神经退行性变。在本研究中，使用原代中脑培养系统，我们测试了突变型α-突触核蛋白是否比WTα-突触核蛋白更有力地激活小胶质细胞，从而导致在fPD中观察到的加速神经退行性变。结果显示，具有A30P或A53T突变的α-突触核蛋白比WTα-突触核蛋白引起更大的小胶质细胞激活。此外，小胶质细胞激活的程度与WT和突变型α-突触核蛋白诱导的多巴胺能神经毒性程度平行。突变型α-突触核蛋白还通过NADPH氧化酶（PHOX）比WTα-突触核蛋白诱导更多的活性氧产生，并且PHOX激活与巨噬细胞抗原-1（Mac-1）受体的直接激活相关，而不是通过清道夫受体的α-突触核蛋白内化。这些结果首次证明小胶质细胞在突变型α-突触核蛋白诱导的增强神经毒性中也起关键作用。
