期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 76, 期 23, 页码 4589-4611出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-019-03203-4
关键词
Parkinson; Ubiquitin; Kinase; Parkin; PINK1; Mitochondria
资金
- Canada Research Chairs [950-229792] Funding Source: Medline
- CIHR [PJT-153274] Funding Source: Medline
- Natural Sciences and Engineering Research Council of Canada [RGPIN-06497] Funding Source: Medline
- Michael J. Fox Foundation for Parkinson's Research [14681] Funding Source: Medline
- Parkinson Society Canada [2017-1277] Funding Source: Medline
- Canada First Research Excellence Fund [1c-II-5] Funding Source: Medline
Parkinson's disease (PD) is a degenerative movement disorder resulting from the loss of specific neuron types in the midbrain. Early environmental and pathophysiological studies implicated mitochondrial damage and protein aggregation as the main causes of PD. These findings are now vindicated by the characterization of more than 20 genes implicated in rare familial forms of the disease. In particular, two proteins encoded by the Parkin and PINK1 genes, whose mutations cause early-onset autosomal recessive PD, function together in a mitochondrial quality control pathway. In this review, we will describe recent development in our understanding of their mechanisms of action, structure, and function. We explain how PINK1 acts as a mitochondrial damage sensor via the regulated proteolysis of its N-terminus and the phosphorylation of ubiquitin tethered to outer mitochondrial membrane proteins. In turn, phospho-ubiquitin recruits and activates Parkin via conformational changes that increase its ubiquitin ligase activity. We then describe how the formation of polyubiquitin chains on mitochondria triggers the recruitment of the autophagy machinery or the formation of mitochondria-derived vesicles. Finally, we discuss the evidence for the involvement of these mechanisms in physiological processes such as immunity and inflammation, as well as the links to other PD genes.
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