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.
Pubmed ID: 30404819 RIS Download
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THIS RESOURCE IS NO LONGER IN SERVICE. Documented on January 9, 2023. An aggregated data platform for genome sequencing data created by a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community. The data set provided on this website spans 61,486 unrelated individuals sequenced as part of various disease-specific and population genetic studies. They have removed individuals affected by severe pediatric disease, so this data set should serve as a useful reference set of allele frequencies for severe disease studies. All of the raw data from these projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects. They ask that you not publish global (genome-wide) analyses of these data until after the ExAC flagship paper has been published, estimated to be in early 2015. If you''re uncertain which category your analyses fall into, please email them. The aggregation and release of summary data from the exomes collected by the Exome Aggregation Consortium has been approved by the Partners IRB (protocol 2013P001477, Genomic approaches to gene discovery in rare neuromuscular diseases).
View all literature mentionsAn observational longitudinal clinical study partnership to identify and validate biomarkers of Parkinson disease (PD) progression and provide easy and open web-based access to the comprehensive set of correlated clinical data and biospecimens, information, and biosamples acquired from PD and age and gender matched healthy control subjects to the research community. The data and specimens have been collected in a standardized manner under strict protocols and includes clinical (demographic, motor and non-motor, cognitive and neurobehavioral), imaging (raw and processed MRI, SPECT and DAT), and blood chemistry and hematology subject assessments and biospecimen inventories (serum, plasma, whole blood, CSF, DNA, RNA and urine). All data are de-identified to protect patient privacy. PPMI will be carried out over five years at 21 clinical sites in the United States and Europe and requires the participation of 400 Parkinson's patients and 200 control participants. The PPMI database provides researchers with access to correlated clinical and imaging data, along with annotated biospecimens, all available within an open access system that encourages data sharing (http://www.ppmi-info.org/access-data-specimens/). The website hosts an Ongoing Analysis section to keep the scientific community apprised of analyses being completed, in hopes of stimulating collaborations between researchers who are using PPMI data and specimens.
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View all literature mentionsDatabase that aggregates exome and genome sequencing data from large-scale sequencing projects. The gnomAD data set contains individuals sequenced using multiple exome capture methods and sequencing chemistries. Raw data from the projects have been reprocessed through the same pipeline, and jointly variant-called to increase consistency across projects.
View all literature mentionsCollection of data of protein sequence and functional information. Resource for protein sequence and annotation data. Consortium for preservation of the UniProt databases: UniProt Knowledgebase (UniProtKB), UniProt Reference Clusters (UniRef), and UniProt Archive (UniParc), UniProt Proteomes. Collaboration between European Bioinformatics Institute (EMBL-EBI), SIB Swiss Institute of Bioinformatics and Protein Information Resource. Swiss-Prot is a curated subset of UniProtKB.
View all literature mentionsAn efficient software tool to utilize update-to-date information to functionally annotate genetic variants detected from diverse genomes (including human genome hg18, hg19, as well as mouse, worm, fly, yeast and many others). Given a list of variants with chromosome, start position, end position, reference nucleotide and observed nucleotides, ANNOVAR can perform: 1. gene-based annotation. 2. region-based annotation. 3. filter-based annotation. 4. other functionalities. (entry from Genetic Analysis Software)
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