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
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