Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures
Impairment of the ubiquitin-proteasome system causes dopaminergic cell death and inclusion body formation in ventral mesencephalic cultures
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DOI：
10.1046/j.1471-4159.2002.00821.x
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发表时间：
2002-04-01
影响因子：
4.7
通讯作者：
Olanow, CW
中科院分区：
文献类型：
--
作者：
McNaught, KS;Mytilineou, C;Olanow, CW
α-突触核蛋白、帕金蛋白和泛素C-末端水解酶L1的突变以及26/20 S蛋白酶体的缺陷导致家族性和散发性帕金森病（PD）的发生或与之相关。这表明泛素-蛋白酶体系统（UPS）降解异常蛋白的失败可能是PD中发生的黑质变性和路易体形成的基础。为了探讨这一概念，我们研究了乳胱氨酸介导的抑制26/20 S蛋白酶体功能和泛素醛（乌巴）诱导的泛素C-末端水解酶（UCH）活性在胎鼠腹侧中脑培养物的损害的影响。我们证明，lactacystin和乌巴引起浓度依赖性和优先变性的多巴胺能神经元。26/20 S蛋白酶体功能的抑制伴随着α-突触核蛋白和泛素的积累，以及这些蛋白质免疫反应性的包涵体的形成，在VM神经元的细胞质中。UCH的抑制与VM神经元细胞质中泛素免疫反应性的丧失相关，但α-突触核蛋白染色明显和局部增加，这可能代表VM神经元中包涵体的形成。这些发现提供了直接的证据表明，受损的蛋白质清除可以诱导多巴胺能细胞死亡和蛋白质包涵体的形成VM神经元。这项研究支持的概念，在UPS的缺陷可能是黑质病理的家族性和散发性形式的PD。
Mutations in a-synuclein, parkin and ubiquitin C-terminal hydrolase L1, and defects in 26/20S proteasomes, cause or are associated with the development of familial and sporadic Parkinson's disease (PD). This suggests that failure of the ubiquitin-proteasome system (UPS) to degrade abnormal proteins may underlie nigral degeneration and Lewy body formation that occur in PD. To explore this concept, we studied the effects of lactacystin-mediated inhibition of 26/20S proteasomal function and ubiquitin aldehyde (UbA)-induced impairment of ubiquitin C-terminal hydrolase (UCH) activity in fetal rat ventral mesencephalic cultures. We demonstrate that both lactacystin and UbA caused concentration-dependent and preferential degeneration of dopaminergic neurons. Inhibition of 26/20S proteasomal function was accompanied by the accumulation of alpha-synuclein and ubiquitin, and the formation of inclusions that were immunoreactive for these proteins, in the cytoplasm of VM neurons. Inhibition of UCH was associated with a loss of ubiquitin immunoreactivity in the cytoplasm of VM neurons, but there was a marked and localized increase in a-synuclein staining which may represent the formation of inclusions bodies in VM neurons. These findings provide direct evidence that impaired protein clearance can induce dopaminergic cell death and the formation of proteinaceous inclusion bodies in VM neurons. This study supports the concept that defects in the UPS may underlie nigral pathology in familial and sporadic forms of PD.