Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis
Inducible expression of mutant α-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis
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DOI：
10.1093/hmg/10.9.919
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发表时间：
2001-04-15
影响因子：
3.5
通讯作者：
Ross, CA
中科院分区：
文献类型：
--
作者：
Tanaka, Y;Engelender, S;Ross, CA
帕金森病（PD）是一种常见的进行性神经退行性疾病，由黑质中多巴胺能神经元的丧失引起。尽管在常染色体显性帕金森病中已发现α-突触核蛋白突变，但多巴胺能神经细胞死亡发生的机制仍不清楚。由引起家族性帕金森病的另外两个基因 Parkin 和 UCH-L1 编码的蛋白质参与泛素蛋白酶体途径的调节，表明泛素蛋白酶体途径的失调参与了这些突变引起帕金森病的机制。 α-突触核蛋白表现出蛋白酶体活性降低，但没有直接毒性。当用亚毒性浓度的外源蛋白酶体抑制剂处理时，表达突变型α-突触核蛋白的细胞表现出对凋亡细胞死亡的敏感性增加。细胞凋亡伴随着线粒体去极化以及caspase-3和-9的升高，并被环孢菌素A阻断。这些数据表明突变体α-突触核蛋白的表达导致对蛋白酶体活性受损的敏感性，导致线粒体异常和神经元细胞死亡。
Parkinson's disease (PD) is a common progressive neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra, Although mutations in alpha -synuclein have been identified in autosomal dominant PD, the mechanism by which dopaminergic neural cell death occurs remains unknown. Proteins encoded by two other genes in which mutations cause familial PD, parkin and UCH-L1, are involved in regulation of the ubiquitin-proteasome pathway, suggesting that dysregulation of the ubiquitin-proteasome pathway is involved in the mechanism by which these mutations cause PD, We established inducible PC12 cell lines in which wild-type or mutant alpha -synuclein can be de-repressed by removing doxycycline, Differentiated PC12 cell lines expressing mutant alpha -synuclein showed decreased activity of proteasomes without direct toxicity, Cells expressing mutant alpha -synuclein showed increased sensitivity to apoptotic cell death when treated with sub-toxic concentrations of an exogenous proteasome inhibitor. Apoptosis was accompanied by mitochondrial depolarization and elevation of caspase-3 and -9, and was blocked by cyclosporin A, These data suggest that expression of mutant alpha -synuclein results in sensitivity to impairment of proteasome activity, leading to mitochondrial abnormalities and neuronal cell death.