Identification of genes that modify ataxin-1-induced neurodegeneration
Abstract
A growing number of human neurodegenerative diseases result from the expansion of a glutamine repeat in the protein that causes the disease. Spinocerebellar ataxia type 1 (SCA1) is one such disease-caused by expansion of a polyglutamine tract in the protein ataxin-1. To elucidate the genetic pathways and molecular mechanisms underlying neuronal degeneration in this group of diseases, we have created a model system for SCA1 by expressing the full-length human SCA1 gene in Drosophila. Here we show that high levels of wild-type ataxin-1 can cause degenerative phenotypes similar to those caused by the expanded protein. We conducted genetic screens to identify genes that modify SCA1-induced neurodegeneration. Several modifiers highlight the role of protein folding and protein clearance in the development of SCA1. Furthermore, new mechanisms of polyglutamine pathogenesis were revealed by the discovery of modifiers that are involved in RNA processing, transcriptional regulation and cellular detoxification. These findings may be relevant to the treatment of polyglutamine diseases and, perhaps, to other neurodegenerative diseases, such as Alzheimer's and Parkinson's disease.
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Other genetic screens of polyQ toxicity have uncovered RNA-binding proteins, but those genes do not overlap with the modifiers presented in this study.
“Other genetic screens of polyQ toxicity have also uncovered RNA-binding proteins (77–79), although those genes identified do not overlap with the modifiers presented in this study.”
From Functional genomic screen and network analysis reveal novel modifiers of tauopathy dissociated from tau phosphorylation (2011) · cites this paper as [77]
Targeted expression of polyglutamine-expanded mutant ATXN1 in the Drosophila eye causes retinal depigmentation, disruption of the structured eye pattern and retinal degeneration.
“we utilized a Drosophila model of SCA1 (Fernandez-Funez et al., 2000) in which targeted expression of polyglutamine-expanded mutant ATXN1 in the eye causes retinal depigmentation, disruption of the structured eye pattern and retinal degeneration (Fig. 3B,F,J).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Fernandez-Funez et al., 2000
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“…understand the disease pathogenesis better and to identify an effector protein that can be potentially used as a therapeutic target in SCA1, we examined candidate proteins identified from our previous physical interaction or genetic modifier studies (Fernandez-Funez et al., 2000; Lim et al., 2006).”
BackgroundMethodSelf-citation
- Authors
- Fernandez-Funez, P., Nino-Rosales, M. L., de Gouyon, B., She, W.-C., Luchak, J. M., Martinez, P., Turiegano, E., Benito, J., Capovilla, M., Skinner, P. J., McCall, A., Canal, I., Orr, H. T., Zoghbi, H. Y., & Botas, J.
- Affiliations
- University of Minnesota (US)
- Universidad Autónoma de Madrid (ES)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Botas, Juan
- Venue
- Nature
- Published
- 2000-11
- Volume
- 408
- Issue
- 6808
- Pages
- 101-106
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1617816798
- Cited by
- 661
- References
- 1
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 11 · 2023: 15 · 2022: 10 · 2021: 17 · 2020: 15 · 2019: 7 · 2018: 20 · 2017: 12 · 2016: 19 · 2015: 23 · 2014: 21 · 2013: 32 · 2012: 23
- FWCI
- 17.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- spinocerebellar ataxia type 1, ataxin-1, polyglutamine expansion, neurodegeneration, genetic modifiers, Drosophila model, protein folding, protein clearance, RNA processing, transcriptional regulation, cellular detoxification, polyglutamine diseases, genetic screen
- MeSH terms
- Ataxins, Ataxin-1, Animals, Inclusion Bodies, Disease Models, Animal, Drosophila, Female, Humans, Male, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Phenotype, Retina, Protein Folding, Heat-Shock Response, Neurodegenerative Diseases, Spinocerebellar Ataxias, Animals, Genetically Modified
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