Phosphorylation of Parkin at serine 65 is essential for its activation in vivo
Autor: | Alan R. Prescott, Graeme Ball, Kyle Fears, Miratul M. K. Muqit, Pentti J. Tienari, Axel Knebel, Johanna Eerola-Rautio, Riccardo Brambilla, Sophie Burel, Lambert Montava-Garriga, Simon Philip Brooks, Odetta Antico, Anu Suomalainen, Ayse Ulusoy, Rachel Hills, Olga Corti, François Mouton-Liger, Eino Palin, Ian G. Ganley, Donato A. Di Monte, Kristin Balk, Jevgenia Tamjar, Thomas G. McWilliams, Laura Smith, François Singh, Stephen B. Dunnett, Risto Pohjolan-Pirhonen, Atul Kumar, Sidi Mohamed Hassoun, Erica Barini, Miko Valori |
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Přispěvatelé: | Medicum, Research Programs Unit, Doctoral Programme in Biomedicine, Research Programme for Molecular Neurology, Neuroscience Center, University of Helsinki, Clinicum, Pentti Tienari / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Neurosciences, Neurologian yksikkö, University Management, Anu Wartiovaara / Principal Investigator, HUS Neurocenter |
Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Ubiquitylation Parkinson's disease parkin protein Mitochondrion PARKIN Parkin Parkinson's disease 3124 Neurology and psychiatry Parkin pathology [Mitochondria] Mice Ubiquitin genetics [Parkinson Disease] Mitophagy Serine metabolism [Protein Kinases] Phosphorylation lcsh:QH301-705.5 genetics [Ubiquitin-Protein Ligases] STRIATUM metabolism [Serine] General Neuroscience Neurodegeneration genetics [Protein Kinases] 1184 Genetics developmental biology physiology neurodegeneration genetics [Serine] Parkinson Disease UBIQUITIN E3 LIGASE Cell biology Mitochondria AUTOPHAGY PTEN-induced putative kinase Research Article Ubiquitin-Protein Ligases Immunology metabolism [Parkinson Disease] PINK1 Mice Transgenic Biology General Biochemistry Genetics and Molecular Biology 03 medical and health sciences metabolism [Ubiquitin-Protein Ligases] ddc:570 medicine Animals Humans genetics [Phosphorylation] Research Autophagy 3112 Neurosciences medicine.disease metabolism [Mitochondria] pathology [Parkinson Disease] nervous system diseases 030104 developmental biology lcsh:Biology (General) biology.protein 1182 Biochemistry cell and molecular biology genetics [Mitochondria] Protein Kinases |
Zdroj: | Open Biology 'Open Biology ', vol: 8, pages: 180108-1-180108-18 (2018) Open biology 8(11), 180108 (2018). doi:10.1098/rsob.180108 Open Biology, Vol 8, Iss 11 (2018) |
ISSN: | 2046-2441 |
DOI: | 10.1098/rsob.180108 |
Popis: | Mutations in PINK1 and Parkin result in autosomal recessive Parkinson's disease (PD). Cell culture and in vitro studies have elaborated the PINK1-dependent regulation of Parkin and defined how this dyad orchestrates the elimination of damaged mitochondria via mitophagy. PINK1 phosphorylates ubiquitin at serine 65 (Ser65) and Parkin at an equivalent Ser65 residue located within its N-terminal ubiquitin-like domain, resulting in activation; however, the physiological significance of Parkin Ser65 phosphorylation in vivo in mammals remains unknown. To address this, we generated a Parkin Ser65Ala (S65A) knock-in mouse model. We observe endogenous Parkin Ser65 phosphorylation and activation in mature primary neurons following mitochondrial depolarization and reveal this is disrupted in Parkin S65A/S65A neurons. Phenotypically, Parkin S65A/S65A mice exhibit selective motor dysfunction in the absence of any overt neurodegeneration or alterations in nigrostriatal mitophagy. The clinical relevance of our findings is substantiated by the discovery of homozygous PARKIN ( PARK2 ) p.S65N mutations in two unrelated patients with PD. Moreover, biochemical and structural analysis demonstrates that the Parkin S65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease. |
Databáze: | OpenAIRE |
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