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

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

Author information

1
Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and.
2
Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; andSheffield RNAi Screening Facility.
3
Department of Cell Physiology and Medicine, University of Geneva, 1205 Geneva, Switzerland.
4
Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, United Kingdom; and a.whitworth@sheffield.ac.uk.

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.

PMID:
24912190
PMCID:
PMC4060696
DOI:
10.1073/pnas.1321207111
[Indexed for MEDLINE]
Free PMC Article

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