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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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Cell Line
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Drosophila Proteins / genetics
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Drosophila Proteins / metabolism
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Drosophila melanogaster / cytology
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Drosophila melanogaster / genetics
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Drosophila melanogaster / metabolism
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F-Box Proteins / genetics
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F-Box Proteins / metabolism
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F-Box-WD Repeat-Containing Protein 7
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Gene Expression Regulation
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Genome-Wide Association Study / methods*
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HeLa Cells
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Humans
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Immunoblotting
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Membrane Potential, Mitochondrial / genetics
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Membrane Potential, Mitochondrial / physiology
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Microscopy, Confocal
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Mitochondria / genetics
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Mitochondria / metabolism
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Mitochondria / physiology
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Mitophagy / genetics*
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Parkinson Disease / genetics*
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Parkinson Disease / metabolism
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Protein Kinases / genetics
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Protein Kinases / metabolism
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RNA Interference*
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Reverse Transcriptase Polymerase Chain Reaction
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Sterol Regulatory Element Binding Protein 1 / genetics*
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Sterol Regulatory Element Binding Protein 1 / metabolism
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
Substances
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Cell Cycle Proteins
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Drosophila Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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SREBF1 protein, human
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Sterol Regulatory Element Binding Protein 1
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Ubiquitin-Protein Ligases
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parkin protein
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Protein Kinases
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PTEN-induced putative kinase