Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity
Expression of mutant α-synuclein causes increased susceptibility to dopamine toxicity
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DOI：
10.1093/hmg/9.18.2683
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发表时间：
2000-11-01
影响因子：
3.5
通讯作者：
Schapira, AHV
中科院分区：
文献类型：
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作者：
Tabrizi, SJ;Orth, M;Schapira, AHV
α-突触核蛋白基因的突变已经在常染色体显性帕金森氏病（PD）中被鉴定，过表达野生型人α-突触核蛋白的转基因小鼠在纹状体中产生运动损伤、神经元内包涵体和多巴胺能末梢的损失。为了研究突变体α-突触核蛋白毒性介导的作用机制，我们已经产生了稳定的，在人源HEK 293细胞中表达野生型或PD相关突变体（G209 A）α-突触核蛋白的诱导型细胞模型。野生型或突变体α-突触核蛋白的表达增加导致与囊泡（包括单胺能）隔室相关的细胞质聚集体的形成。与野生型蛋白表达相比，突变体α-突触核蛋白的表达诱导对多巴胺毒性的敏感性显著增加。这些结果为在PD G209 A突变体α-突触核蛋白家族中观察到的优先多巴胺能神经元变性提供了解释，并表明类似的机制可能是散发性PD中细胞死亡的基础或促成细胞死亡。
Mutations of the alpha -synuclein gene have been identified in autosomal dominant Parkinson's disease (PD), Transgenic mice overexpressing wild-type human alpha -synuclein develop motor impairments, intraneuronal inclusions and loss of dopaminergic terminals in the striatum, To study the mechanism of action through which mutant alpha -synuclein toxicity is mediated, we have generated stable, inducible cell models expressing wild-type or PD-associated mutant (G209A) alpha -synuclein in human-derived HEK293 cells. Increased expression of either wild-type or mutant alpha -synuclein resulted in the formation of cytoplasmic aggregates which were associated with the vesicular (including monoaminergic) compartment. Expression of mutant alpha -synuclein induced a significant increase in sensitivity to dopamine toxicity compared with the wild-type protein expression. These results provide an explanation for the preferential dopaminergic neuronal degeneration seen in both the PD G209A mutant alpha -synuclein families and suggest that similar mechanisms may underlie or contribute to cell death in sporadic PD.