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

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 d...

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Autores principales: Chin, Lih-Shen, Li, Lian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702311/
https://www.ncbi.nlm.nih.gov/pubmed/26740872
http://dx.doi.org/10.1186/s40035-015-0049-6
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author Chin, Lih-Shen
Li, Lian
author_facet Chin, Lih-Shen
Li, Lian
author_sort Chin, Lih-Shen
collection PubMed
description 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.
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spelling pubmed-47023112016-01-07 Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment Chin, Lih-Shen Li, Lian Transl Neurodegener Review 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. BioMed Central 2016-01-06 /pmc/articles/PMC4702311/ /pubmed/26740872 http://dx.doi.org/10.1186/s40035-015-0049-6 Text en © Chin and Li. 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Review
Chin, Lih-Shen
Li, Lian
Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title_full Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title_fullStr Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title_full_unstemmed Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title_short Ubiquitin phosphorylation in Parkinson’s disease: Implications for pathogenesis and treatment
title_sort ubiquitin phosphorylation in parkinson’s disease: implications for pathogenesis and treatment
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702311/
https://www.ncbi.nlm.nih.gov/pubmed/26740872
http://dx.doi.org/10.1186/s40035-015-0049-6
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