Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-06, Vol.111 (23), p.8494-8499
• Main Authors: Ivatt, Rachael M., Sanchez-Martinez, Alvaro, Godena, Vinay K., Brown, Stephen, Ziviani, Elena, Whitworth, Alexander J.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Line; Cholesterols; Drosophila; Drosophila melanogaster - cytology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; F-Box Proteins - genetics; F-Box Proteins - metabolism; F-Box-WD Repeat-Containing Protein 7; Fatty acids; Gene Expression Regulation; Genes; Genetic screening; Genetics; Genome-Wide Association Study - methods; Genomes; HeLa Cells; Hep G2 cells; Homeostasis; Humans; Immunoblotting; Lipids; Membrane Potential, Mitochondrial - genetics; Membrane Potential, Mitochondrial - physiology; Microscopy, Confocal; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondria - physiology; Mitophagy - genetics; Mutation; Neurons; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson's disease; Protein Kinases - genetics; Protein Kinases - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleic acid; RNA; RNA Interference; Small interfering RNA; Sterol Regulatory Element Binding Protein 1 - genetics; Sterol Regulatory Element Binding Protein 1 - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1321207111

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.