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

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 degradati...

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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.
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container_title Proceedings of the National Academy of Sciences - PNAS
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creator Ivatt, Rachael M.
Sanchez-Martinez, Alvaro
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description 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.
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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
title Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy
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