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

Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8494-9. doi: 10.1073/pnas.1321207111. Epub 2014 May 27.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / cytology
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism
  • F-Box-WD Repeat-Containing Protein 7
  • Gene Expression Regulation
  • Genome-Wide Association Study / methods*
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Membrane Potential, Mitochondrial / genetics
  • Membrane Potential, Mitochondrial / physiology
  • Microscopy, Confocal
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mitochondria / physiology
  • Mitophagy / genetics*
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • RNA Interference*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sterol Regulatory Element Binding Protein 1 / genetics*
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Cell Cycle Proteins
  • Drosophila Proteins
  • F-Box Proteins
  • F-Box-WD Repeat-Containing Protein 7
  • FBXW7 protein, human
  • SREBF1 protein, human
  • Sterol Regulatory Element Binding Protein 1
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Protein Kinases
  • PTEN-induced putative kinase