The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.
The roles of PINK1, parkin, and mitochondrial fidelity in Parkinson's disease.
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DOI：
10.1016/j.neuron.2014.12.007
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发表时间：
2015-01-21
期刊：
影响因子：
16.2
通讯作者：
Youle RJ
中科院分区：
文献类型：
--
作者：
Pickrell AM;Youle RJ
了解遗传性帕金森病中突变基因的功能，可以深入了解疾病的病因，并揭示细胞生物学的新途径。尽管许多基因的突变或变异增加了帕金森病的易感性，但只有少数帕金森综合征的单基因原因被确定。生化和遗传研究表明，常染色体隐性帕金森氏症中突变的两个基因的产物PINK 1和Parkin通常在同一途径中共同作用以控制线粒体质量控制，这支持了之前关于线粒体损伤与帕金森氏症有关的证据。PINK1在受损线粒体的外膜上积累，激活帕金E3泛素连接酶活性，并将帕金招募到功能障碍的线粒体。然后，帕金泛素化外线粒体膜蛋白，以触发选择性自噬。本文综述了PINK1和Parkin在细胞内发挥的正常功能，它们的分子作用机制以及它们丧失的病理生理后果。
Understanding the function of genes mutated in hereditary forms of Parkinson's disease yields insight into disease etiology and reveals new pathways in cell biology. Although mutations or variants in many genes increase the susceptibility to Parkinson's disease, only a handful of monogenic causes of Parkinsonism have been identified. Biochemical and genetic studies reveal that the products of two genes that are mutated in autosomal recessive Parkinsonism, PINK1 and Parkin, normally work together in the same pathway to govern mitochondrial quality control, bolstering previous evidence that mitochondrial damage is involved in Parkinson's disease. PINK1 accumulates on the outer membrane of damaged mitochondria, activates Parkin's E3 ubiquitin ligase activity and recruits Parkin to the dysfunctional mitochondrion. Then, Parkin ubiquitinates outer mitochondrial membrane proteins to trigger selective autophagy. This review covers the normal functions that PINK1 and Parkin play within cells, their molecular mechanisms of action, and the pathophysiological consequences of their loss.