Phosphorylation of Parkin at serine 65 is essential for its activation in vivo

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McWilliams , T , Barini , E , Pohjolan-Pirhonen , R , Brooks , S P , Singh , F , Burel , S , Balk , K , Kumar , A , Montava-Garriga , L , Prescott , A R , Hassoun , S M , Mouton-Liger , F , Ball , G , Hills , R , Knebel , A , Ulusoy , A , Di Monte , D A , Tamjar , J , Antico , O , Fears , K , Smith , L , Brambilla , R , Palin , E , Valori , M , Eerola-Rautio , J , Tienari , P , Corti , O , Dunnett , S B , Ganley , I G , Suomalainen , A & Muqit , M M K 2018 , ' Phosphorylation of Parkin at serine 65 is essential for its activation in vivo ' , Open biology , vol. 8 , no. 11 , 180108 .

Title: Phosphorylation of Parkin at serine 65 is essential for its activation in vivo
Author: McWilliams, Thomas; Barini, Erica; Pohjolan-Pirhonen, Risto; Brooks, Simon P.; Singh, François; Burel, Sophie; Balk, Kristin; Kumar, Atul; Montava-Garriga, Lambert; Prescott, Alan R.; Hassoun, Sidi Mohamed; Mouton-Liger, François; Ball, Graeme; Hills, Rachel; Knebel, Axel; Ulusoy, Ayse; Di Monte, Donato A.; Tamjar, Jevgenia; Antico, Odetta; Fears, Kyle; Smith, Laura; Brambilla, Riccardo; Palin, Eino; Valori, Miko; Eerola-Rautio, Johanna; Tienari, Pentti; Corti, Olga; Dunnett, Stephen B.; Ganley, Ian G.; Suomalainen, Anu; Muqit, Miratul M.K.
Contributor organization: Medicum
Research Programs Unit
Doctoral Programme in Biomedicine
Research Programme for Molecular Neurology
Neuroscience Center
University of Helsinki
Pentti Tienari / Principal Investigator
Genome-Scale Biology (GSB) Research Program
Department of Neurosciences
Neurologian yksikkö
University Management
Anu Wartiovaara / Principal Investigator
HUS Neurocenter
Date: 2018-11-07
Language: eng
Number of pages: 18
Belongs to series: Open biology
ISSN: 2046-2441
Abstract: 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 ParkinS65A/S65A neurons. Phenotypically, ParkinS65A/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 ParkinS65N/S65N mutant is pathogenic and cannot be activated by PINK1. Our findings highlight the central role of Parkin Ser65 phosphorylation in health and disease.
Subject: 1182 Biochemistry, cell and molecular biology
Parkinson's disease
3112 Neurosciences
Parkinson's disease
3124 Neurology and psychiatry
1184 Genetics, developmental biology, physiology
Peer reviewed: Yes
Usage restriction: openAccess
Self-archived version: publishedVersion

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