The Roles of PINK1, Parkin and Mitochondrial Fidelity in Parkinson's Disease

By Alicia M. Pickrell, R. Youle. Neuron, 2015

2,096 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/f9c141694504cd122ff841ddce7d059d4e5f1792

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Citations in the corpus

Role of pyroptosis in inflammation and cancer (2022, background): “It is reported that the PINK1-PARK2 pathway is usually considered to function in the pathogenesis of Parkinson’s disease [74].”
Mitochondria-lysosome contacts regulate mitochondrial fission via Rab7 GTP hydrolysis (2018, neutral): “Next, we analyzed whether mitochondria-lysosome contacts represented sites of bulk protein transfer or mitochondrial degradation either directly through mitochondrial-derived vesicles (MDVs) fusing with lysosomes 7 or indirectly through mitophagy 6 .”
Brain metabolism in health, aging, and neurodegeneration (2017, positive): “Importantly, mutations in multiple genes that cause early-onset inherited forms of PD (a-synuclein, Parkin, PINK1, LRRK2, DJ-1) result in mitochondrial dysfunction (Pickrell & Youle, 2015).”
Neuronal Cell Death. (2018, neutral): “p62 is often found bound to misfolded protein aggregates that accumulate in neurodegenerative diseases (257), while the LIR-domain proteins NDF2 and optineurin, but not p62, play a major role in mitophagy of mitochondria marked for degradation by the Pink1 (PARK6)/Parkin (PARK2) pathway, where mutat”
The PI3K pathway in human disease (2017, neutral): “A recent report offered evidence for an alternative pathway of PTEN inactivation driven by somatic disruption of PARK2 , which encodes Parkin, an E3 ligase involved in the elimination of dysfunctional mitochondria by mitophagy (Gupta et al., 2017; Pickrell and Youle, 2015).”
Oxidative Stress: A Key Modulator in Neurodegenerative Diseases (2019, background): “Proteins PINK 1 and Parkin are associated with autophagy for damaged mitochondria, whereas functional impairment of these proteins leads to accumulation of damaged mitochondria in cells [115,116].”
Prohibitin 2 Is an Inner Mitochondrial Membrane Mitophagy Receptor (2016, neutral): “StrepII-tagged LC3 (an autophagosomal membrane protein whose cleaved and lipidated form, LC3-II, binds to cargo) (Mizushima et al., 2010) and Parkin, an E3 ligase that translocates to depolarized mitochondria and promotes their degradation by mitophagy (Pickrell and Youle, 2015).”
Mitochondrial dynamics in health and disease: mechanisms and potential targets (2023, background): “Emerging evidence strongly indicates that gene mutations in ﬂ uencing mitochondrial dynamics are crucial to the development of PD. 175 Parkin, a protein encoded by the PARK2 gene, is implicated in PD. 176 A cytosolic ubiquitin E3 ligase protein, Parkin plays an important role in the process of ubiqu”