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

TitleGenome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy.
Publication TypeJournal Article
Year of Publication2014
AuthorsIvatt, RM, Sanchez-Martinez, A, Godena, VK, Brown, S, Ziviani, E, Whitworth, AJ
JournalProc Natl Acad Sci U S A
Volume111
Issue23
Pagination8494-9
Date Published2014 Jun 10
ISSN1091-6490
KeywordsAnimals, Cell Cycle Proteins, Cell Line, Drosophila melanogaster, Drosophila Proteins, F-Box Proteins, Gene Expression Regulation, Genome-Wide Association Study, HeLa Cells, Humans, Immunoblotting, Membrane Potential, Mitochondrial, Microscopy, Confocal, Mitochondria, Mitochondrial Degradation, Parkinson Disease, Protein Kinases, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Sterol Regulatory Element Binding Protein 1, Ubiquitin-Protein Ligases
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.

DOI10.1073/pnas.1321207111
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
Citation Key10.1073/pnas.1321207111
PubMed ID24912190
PubMed Central IDPMC4060696
Grant List089698 / / Wellcome Trust / United Kingdom
G070091 / / Medical Research Council / United Kingdom
GR077544AIA / / Wellcome Trust / United Kingdom
WT089698 / / Wellcome Trust / United Kingdom