Ubiquitin and Parkinson's disease through the looking glass of genetics.
Ubiquitin and Parkinson's disease through the looking glass of genetics.
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DOI：
10.1042/bcj20160498
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发表时间：
2017-04-13
期刊：
影响因子：
--
通讯作者：
Muqit MM
中科院分区：
文献类型：
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作者：
Walden H;Muqit MM
在帕金森病（PD）患者大脑中发现的生化改变表明，细胞应激是多巴胺能神经元丧失的主要驱动因素。氧化应激、线粒体功能障碍和内质网应激导致蛋白质质量控制通路的稳态调节受损，从而使蛋白质错误折叠和聚集增加以及蛋白质降解机制失效。泛素信号在蛋白质质量控制中起着核心作用；然而，在基因研究取得进展之前，泛素系统受损如何与帕金森病相关联的详细机制一直是个谜。α - 突触核蛋白基因（其编码在帕金森病聚集体中错误折叠的主要蛋白质）以及编码泛素调节分子（包括PTEN诱导激酶1（PINK1）、帕金和FBX07）的基因发生突变的发现，为剖析帕金森病中泛素信号中断的分子基础提供了机会，并且这一知识对于开发针对泛素系统的帕金森病新型治疗策略至关重要。
Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.