Cited by 160Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersAmyotrophic Lateral Sclerosis Research

A Genomewide RNA Interference Screen for Modifiers of Aggregates Formation by Mutant Huntingtin in Drosophila

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Zhang, Sheng, Binari, Richard, Zhou, Rui, Perrimon, Norbert·2010·Genetics

Abstract

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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Crossref · 10.1534/genetics.109.112516

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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
Published
2010-04-01
Volume
184
Issue
4
Pages
1165-1179
ISSN
  • 0016-6731 (ISSN-L)
  • 1943-2631
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
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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