title: Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy.
abstract: Genetic analysis of Parkinson disease (PD) has identified several genes whose mutation causes inherited parkinsonism, as well as risk loci for sporadic PD. PTEN-induced kinase 1 (PINK1) and parkin, linked to autosomal recessive PD, act in a common genetic pathway regulating the autophagic degradation of mitochondria, termed mitophagy. We undertook a genome-wide RNAi screen as an unbiased approach to identify genes regulating the PINK1/Parkin pathway. We identified several genes that have a conserved function in promoting mitochondrial translocation of Parkin and subsequent mitophagy, most notably sterol regulatory element binding transcription factor 1 (SREBF1), F-box and WD40 domain protein 7 (FBXW7), and other components of the lipogenesis pathway. The relevance of mechanisms of autosomal recessive parkinsonism to sporadic PD has long been debated. However, with the recent identification of SREBF1 as a risk locus for sporadic PD, our findings suggest a common mechanistic link between autosomal recessive and sporadic PD, and underscore the importance of mitochondrial homeostasis.
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Ivatt
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Sanchez-Martinez
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
authors.forename: Vinay K
authors.initials: VK
authors.lastname: Godena
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; andSheffield RNAi Screening Facility.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brown
authors.affiliation: Department of Cell Physiology and Medicine, University of Geneva, 1205 Geneva, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Ziviani
authors.affiliation: Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and a.whitworth@sheffield.ac.uk.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Whitworth
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D018613:Microscopy, Confocal; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D063306:Mitophagy / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
chemical_list: D018797:Cell Cycle Proteins; D029721:Drosophila Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D011494:Protein Kinases; D051780:Sterol Regulatory Element Binding Protein 1; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C513273:FBXW7 protein, human; C497387:SREBF1 protein, human; C111567:parkin protein