ATAXIN-1 Interacts with the Repressor Capicua in Its Native Complex to Cause SCA1 Neuropathology
Open accessAbstract
Spinocerebellar ataxia type 1 (SCA1) is one of several neurodegenerative diseases caused by expansion of a polyglutamine tract in the disease protein, in this case, ATAXIN-1 (ATXN1). A key question in the field is whether neurotoxicity is mediated by aberrant, novel interactions with the expanded protein or whether its wild-type functions are augmented to a deleterious degree. We examined soluble protein complexes from mouse cerebellum and found that the majority of wild-type and expanded ATXN1 assembles into large stable complexes containing the transcriptional repressor Capicua. ATXN1 directly binds Capicua and modulates Capicua repressor activity in Drosophila and mammalian cells, and its loss decreases the steady-state level of Capicua. Interestingly, the S776A mutation, which abrogates the neurotoxicity of expanded ATXN1, substantially reduces the association of mutant ATXN1 with Capicua in vivo. These data provide insight into the function of ATXN1 and suggest that SCA1 neuropathology depends on native, not novel, protein interactions.
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The importance of a large ATXN1 protein complex for the pathogenesis of SCA1 is established.
“Having established the importance of a large ATXN1 protein complex for the pathogenesis of SCA1 (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Jafar-Nejad et al., 2011)”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Lam et al., 2006
CIC family proteins play a key role in modulating ATXN1 functions and SCA1 pathogenesis.
“the CIC family proteins play a key role in modulating ATXN1 functions and SCA1 pathogenesis (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Fryer et al., 2011; Lee et al., 2011)”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Lam et al., 2006
This transcriptional activity is important for the pathogenesis of SCA1.
“This transcriptional activity is important for the pathogenesis of SCA1 (Lin et al., 2000; Serra et al., 2004; Lam et al., 2006; Cvetanovic et al., 2007; Crespo-Barreto et al., 2010; Cvetanovic et al., 2011; Fryer et al., 2011).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Lam et al., 2006
ATXN1 protein binds to CIC family transcription factors and regulates transcription of target genes in vitro and in vivo.
“The ATXN1 protein binds to the CIC family of transcription factors and regulates the transcription of target genes in vitro in cell culture systems (Lam et al., 2006) as well as in vivo in mice (Crespo-Barreto et al., 2010; Fryer et al., 2011).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Lam et al., 2006
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InfluentialSelf-citation
- Authors
- Lam, Y. C., Bowman, A. B., Jafar-Nejad, P., Lim, J., Richman, R., Fryer, J. D., Hyun, E. D., Duvick, L. A., Orr, H. T., Botas, J., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- University of Minnesota (US)
- Corresponding author
- Zoghbi, Huda Y.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2006-12
- Volume
- 127
- Issue
- 7
- Pages
- 1335-1347
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2097978324
- Cited by
- 326
- References
- 0
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 9 · 2023: 16 · 2022: 15 · 2021: 11 · 2020: 25 · 2019: 14 · 2018: 25 · 2017: 18 · 2016: 10 · 2015: 20 · 2014: 19 · 2013: 18 · 2012: 17
- FWCI
- 5.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 2456 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD024064)
- National Institute of Neurological Disorders and Stroke (NS22920, NS27699, NS45667)
- 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, Capicua, polyglutamine expansion, protein-protein interaction, transcriptional repressor, neurodegeneration, cerebellum, Drosophila
- MeSH terms
- Ataxins, Ataxin-1, Amino Acid Sequence, Animals, Brain, Cerebellum, Drosophila, Eye Abnormalities, Humans, Molecular Sequence Data, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Repressor Proteins, Transcription, Genetic, Wings, Animal, Conserved Sequence, Sequence Homology, Amino Acid, Spinocerebellar Ataxias, Animals, Genetically Modified, Mice
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