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Review
. 2016 Jan 6:5:1.
doi: 10.1186/s40035-015-0049-6. eCollection 2016.

Ubiquitin phosphorylation in Parkinson's disease: Implications for pathogenesis and treatment

Lih-Shen Chin  1 , Lian Li  1
Affiliations
Review

Ubiquitin phosphorylation in Parkinson's disease: Implications for pathogenesis and treatment

Lih-Shen Chin et al. Transl Neurodegener. .

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.

Keywords: Mitochondrial quality control; Mitophagy; PINK1; Parkin; Parkinson’s disease; Ubiquitin phosphorylation; Ubiquitin-protein ligase.

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Figures

Fig. 1
Fig. 1
PINK1-mediated intramitochondrial signaling in healthy mitochondria. PINK1 is imported into healthy mitochondria through the TOM and TIM complexes and is then cleaved sequentially by mitochondrial processing peptidase (MPP) and PARL to generate a processed form of PINK1 that resides in the intermembrane space. There, PINK1 can phosphorylate mitochondrial chaperone TRAP1 and perhaps also other substrates to regulate the activities of polarized mitochondria, such as respiration and redox control
Fig. 2
Fig. 2
PINK1-mediated phosphorylation of ubiquitin and parkin on damaged mitochondria in facilitation of mitophagy. Mitochondrial damage causes PINK1 localization and activation on the OMM, leading to Ser65-phosphorylation of pre-existing ubiquitin chains conjugated to OMM proteins (1). The phosphorylated ubiquitin recruits parkin, enables Ser65-phosphorylation of parkin by PINK1, and activates parkin (2). The activated parkin ubiquitinates additional OMM proteins (3) and thus provides more substrates for phosphorylation by PINK1 (4), leading to further recruitment and activation of parkin (2). This positive feed-forward cycle results in a rapid increase in the local concentration of Ser65-phosphorylated ubiquitin (5), which serves as a signal for recruiting autophagy receptors, such as OPTN and NDP52, to promote mitophagy (6)
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