Genome-wide RNAi screen identifies the Parkinson disease GWAS risk locus SREBF1 as a regulator of mitophagy
Open accessAbstract
Significance: This study presents the first results, to our knowledge, of a whole-genome RNAi screen to identify factors that promote Parkin-mediated mitophagy, which have been validated for conservation across species. Top hits comprise several components of the sterol regulatory element binding transcription factor ( SREBF ) lipogenesis pathway, and we show that provision of exogenous lipids can promote the mitophagy pathway. Because SREBF1 has been identified as a risk locus for sporadic Parkinson disease (PD) through genome-wide association studies, the identification of SREBF1 in our screen provides evidence for mechanistic insight into the pathogenesis of sporadic PD. Thus, our functional studies provide the first insight, to our knowledge, into why the master regulator for lipogenesis, SREBF1 , may contribute to sporadic PD and further underscore the impact of dysfunctional mitophagy on pathogenesis.
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Multiple genome-wide siRNA/CRISPR-Cas9 screens have identified mitophagy genes with little overlap between studies.
“Multiple genome-wide siRNA/CRISPR-Cas9 screens have already identified mitophagy genes although with little overlap between studies [15–18].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [15]
The RNAi Screening section (page not provided) describes a genome-wide Drosophila RNAi screen and subsequent human-cell siRNA validation that identified 20 candidate mitophagy genes. It does not compare its hits with those of other studies or establish that overlap between screens was small; it also does not report a CRISPR-Cas9 screen. (LLM, conf=0.84)
Experimental — accuracy not yet measuredLipogenesis plays a role in PINK1 stabilization, as suggested by identification of SREBF1/2 in a genome-wide siRNA screen.
“A role of lipogenesis for PINK1 stabilization has been suggested before by the identification of the SREBF1/2 transcription factors in a genome-wide siRNA screen [15].”
From miRNA family miR-29 inhibits PINK1-PRKN signaling via ATG9A (2026) · cites this paper as [15]
In the RNAi-screen results section (page unavailable), the paper reports that SREBF1 knockdown reduced PINK1 stabilization after mitochondrial depolarization; the Discussion suggests a role for the SREBP lipogenesis pathway. It identifies SREBF2 as a close homolog of SREBF1, but does not identify SREBF2 as a screen hit or show that its knockdown affects PINK1 stabilization. The genome-wide screen used Drosophila RNAi, with subsequent validation in human cells, rather than a genome-wide siRNA screen. (LLM, conf=0.87)
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- Authors
- Ivatt, R. M., Sanchez-Martinez, A., Godena, V. K., Brown, S., Ziviani, E., & Whitworth, A. J.
- Affiliations
- Medical Research Council (GB)
- Medical Research Council Centre for Developmental and Biomedical Genetics, Sheffield S10 2TN, United Kingdom;
- University of Sheffield (GB)
- University of Geneva (CH)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-05-27
- Volume
- 111
- Issue
- 23
- Pages
- 8494-8499
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4060696
- OpenAlex
- W2039276829
- Cited by
- 130
- References
- 8
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 9 · 2023: 5 · 2022: 12 · 2021: 15 · 2020: 11 · 2019: 13 · 2018: 14 · 2017: 14 · 2016: 11 · 2015: 12 · 2014: 1
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- University of Dundee
- Wellcome Trust (WT089698, 084757, GR077544AIA, 089698)
- University College London
- European Commission
- Medical Research Council (MC_G1000735, GR077544AIA, WT089698)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- Parkinson's disease, SREBF1, mitophagy, PINK1, Parkin, FBXW7, lipogenesis, mitochondrial homeostasis, autosomal recessive parkinsonism, sporadic Parkinson disease, RNAi screen, mitochondrial translocation
- MeSH terms
- F-Box-WD Repeat-Containing Protein 7, PTEN-Induced Putative Kinase, Animals, Cell Line, Drosophila melanogaster, Gene Expression Regulation, HeLa Cells, Humans, Mitochondria, Parkinson Disease, Protein Kinases, Immunoblotting, Microscopy, Confocal, Cell Cycle Proteins, Reverse Transcriptase Polymerase Chain Reaction, Drosophila Proteins, RNA Interference, Ubiquitin-Protein Ligases, F-Box Proteins, Sterol Regulatory Element Binding Protein 1, Membrane Potential, Mitochondrial, Genome-Wide Association Study, Mitophagy
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