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.

Subtle alterations of excitatory transmission are linked to presynaptic changes in the hippocampus of PINK1‐deficient mice

“…This neuroprotective role is also in agreement with several lines of evidence indicating that PINK1 can protect cells also from other types of stressors, including proteasomal inhibition, oxidative stress, mitochondrial blockers and apoptotic inducers (Mills et al, ; Matic et al, ; Strappazzon and Cecconi, ). For these reasons, targeting PINK1 pathway might be of therapeutic interest not only in PD and other neurodegenerative conditions (Khalil et al, ; Chin and Li, ), but also in peripheral disorders (Williams and Ding, ).…”

Generation of phospho‐ubiquitin variants by orthogonal translation reveals codon skipping

“…Some experiments presented here used what might be considered a 'high stoichiometry' of pUb, yet the stoichiometry and abundance of different pUb variants in the cell is not yet known. Quantitation based on phosphoproteomic data suggests pUb S65 represents between 0.1% and 20% of the total cellular Ub pool [10,36,37]. Recent data show that pUb S65 is not uniformly distributed in the cell.…”

Targeted mass spectrometry: An emerging powerful approach to unblock the bottleneck in phosphoproteomics

“…It should be noted that alterations in kinase biology and protein phosphorylation is not exclusively occurring in cancer but also in many other common diseases including neuropathies [130][131][132][133][134][135][136][137], myopathies [138][139] and diabetes [140] (table 1). Therefore clinicians from distinct fields could greatly benefit from the advantages offered by targeted phosphoproteomics to detect site-specific phosphorylation events that could serve to diagnose a disease, stratify similar pathologies or even predict whether a patient will respond or not to a specific treatment.…”