A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila
Open accessAbstract
Protein aggregates are a common pathological feature of most neurodegenerative diseases (NDs). Understanding their formation and regulation will help clarify their controversial roles in disease pathogenesis. To date, there have been few systematic studies of aggregates formation in Drosophila, a model organism that has been applied extensively in modeling NDs and screening for toxicity modifiers. We generated transgenic fly lines that express enhanced-GFP-tagged mutant Huntingtin (Htt) fragments with different lengths of polyglutamine (polyQ) tract and showed that these Htt mutants develop protein aggregates in a polyQ-length- and age-dependent manner in Drosophila. To identify central regulators of protein aggregation, we further generated stable Drosophila cell lines expressing these Htt mutants and also established a cell-based quantitative assay that allows automated measurement of aggregates within cells. We then performed a genomewide RNA interference screen for regulators of mutant Htt aggregation and isolated 126 genes involved in diverse cellular processes. Interestingly, although our screen focused only on mutant Htt aggregation, several of the identified candidates were known previously as toxicity modifiers of NDs. Moreover, modulating the in vivo activity of hsp110 (CG6603) or tra1, two hits from the screen, affects neurodegeneration in a dose-dependent manner in a Drosophila model of Huntington's disease. Thus, other aggregates regulators isolated in our screen may identify additional genes involved in the protein-folding pathway and neurotoxicity.
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The Httex1-Q46-eGFP reporter forms aggregates in the eye that can be detected by fluorescence imaging.
“When this Httex1-Q46-eGFP reporter is expressed in the eye, the aggregates can be detected by fluorescence imaging (Fig 4A).”
From Functional unknomics: Systematic screening of conserved genes of unknown function (2023) · cites this paper as [59]
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- Authors
- Zhang, S., Binari, R., Zhou, R., & Perrimon, N.
- Affiliations
- Department of Genetics and
- Howard Hughes Medical Institute (US)
- Corresponding author
- Zhang, Sheng
- Perrimon, Norbert
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-01
- Volume
- 184
- Issue
- 4
- Pages
- 1165-1179
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC2865916
- OpenAlex
- W2069048146
- Cited by
- 160
- References
- 67
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 15 · 2023: 13 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 9 · 2018: 9 · 2017: 12 · 2016: 6 · 2015: 9 · 2014: 15 · 2013: 14 · 2012: 12
- FWCI
- 5.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- Hereditary Disease Foundation
- Leukemia and Lymphoma Society
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- mutant huntingtin, protein aggregation, polyglutamine tract, neurodegenerative diseases, Drosophila, Hsp110, Tra1, protein folding, Huntington's disease model
- MeSH terms
- Huntingtin Protein, Age Factors, Animals, Drosophila melanogaster, Humans, Microtubule-Associated Proteins, Mutation, Peptides, Transcription Factors, Protein Structure, Quaternary, Genomics, Drosophila Proteins, RNA Interference, Genome, Insect, Mutant Proteins, HSP110 Heat-Shock Proteins, Protein Multimerization, High-Throughput Screening Assays
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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