title: Ubiquitin phosphorylation in Parkinson's disease: Implications for pathogenesis and treatment.
abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, characterized primarily by the loss of dopaminergic neurons in substantia nigra. The pathogenic mechanisms of PD remain unclear, and no effective therapy currently exists to stop neurodegeneration in this debilitating disease. The identification of mutations in mitochondrial serine/threonine kinase PINK1 or E3 ubiquitin-protein ligase parkin as the cause of autosomal recessive PD opens up new avenues for uncovering neuroprotective pathways and PD pathogenic mechanisms. Recent studies reveal that PINK1 translocates to the outer mitochondrial membrane in response to mitochondrial depolarization and phosphorylates ubiquitin at the residue Ser65. The phosphorylated ubiquitin serves as a signal for activating parkin and recruiting autophagy receptors to promote clearance of damaged mitochondria via mitophagy. Emerging evidence has begun to indicate a link between impaired ubiquitin phosphorylation-dependent mitophagy and PD pathogenesis and supports the potential of Ser65-phosphorylated ubiquitin as a biomarker for PD. The new mechanistic insights and phenotypic screens have identified multiple potential therapeutic targets for PD drug discovery. This review highlights recent advances in understanding ubiquitin phosphorylation in mitochondrial quality control and PD pathogenesis and discusses how these findings can be translated into novel approaches for PD diagnostic and therapeutic development.
authors.affiliation: Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322 USA.
authors.forename: Lih-Shen
authors.initials: LS
authors.lastname: Chin
authors.affiliation: Department of Pharmacology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322 USA.
authors.forename: Lian
authors.initials: L
authors.lastname: Li
keywords: Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease; Ubiquitin phosphorylation; Ubiquitin-protein ligase