Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes
Abstract
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine tract in ataxin-1 (ATXN1). SCA1 pathogenesis studies support a model in which the expanded glutamine tract causes toxicity by modulating the normal activities of ATXN1. To explore native interactions that modify the toxicity of ATXN1, we generated a targeted duplication of the mouse ataxin-1-like (Atxn1l, also known as Boat) locus, a highly conserved paralog of SCA1, and tested the role of this protein in SCA1 pathology. Using a knock-in mouse model of SCA1 that recapitulates the selective neurodegeneration seen in affected individuals, we found that elevated Atxn1l levels suppress neuropathology by displacing mutant Atxn1 from its native complex with Capicua (CIC). Our results provide genetic evidence that the selective neuropathology of SCA1 arises from modulation of a core functional activity of ATXN1, and they underscore the importance of studying the paralogs of genes mutated in neurodegenerative diseases to gain insight into mechanisms of pathogenesis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 Bowman et al., 2007
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 Bowman et al., 2007
Cited by
Sorted by citations
Dindot, S. V., Antalffy, B. A., Bhattacharjee, M. B., & Beaudet, A. L. (2007) · Human Molecular Genetics · doi:10.1093/hmg/ddm288 · Cited by 418 · see citing works
Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., & Zoghbi, H. Y. (2008) · Nature · doi:10.1038/nature06731 · Cited by 311 · see citing works
Self-citationNishiyama, J., Miura, E., Mizushima, N., Watanabe, M., & Yuzaki, M. (2007) · Autophagy · doi:10.4161/auto.4964 · Cited by 159 · see citing works
Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
Ju, H., Kokubu, H., Todd, T. W., Kahle, J. J., Kim, S., Richman, R., Chirala, K., Orr, H. T., Zoghbi, H. Y., & Lim, J. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.3465-12.2013 · Cited by 31 · see citing works
“Thus, complex for the pathogenesis of SCA1 (Lam et al., 2006; Bowman et al., 2007; Lim et al., 2008; Jafar-Nejad et al., 2011), we next investigated the effects of decreasing NLK protein level by 50% on the formation and maintenance of ATXN1 protein complexes.”
BackgroundResultInfluentialSelf-citation
- Authors
- Bowman, A. B., Lam, Y. C., Jafar-Nejad, P., Chen, H.-K., Richman, R., Samaco, R. C., Fryer, J. D., Kahle, J. J., Orr, H. T., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- University of Minnesota (US)
- Corresponding author
- Zoghbi, Huda Y
- Venue
- Nature Genetics
- Published
- 2007-02-18
- Volume
- 39
- Issue
- 3
- Pages
- 373-379
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2017309058
- Cited by
- 86
- References
- 0
- Citations by year
- 2026: 2 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 4 · 2020: 13 · 2019: 2 · 2018: 4 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 8 · 2012: 6
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS 27699, NS45667, NS-22920, R01NS045667)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 024064, P30HD024064)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- spinocerebellar ataxia type 1, ataxin-1, boats, gene duplication, polyglutamine expansion, Capicua, protein complexes, neurodegeneration, knock-in mice, paralogs
- MeSH terms
- Ataxins, Ataxin-1, Animals, Cells, Cultured, Cerebellum, Mice, Inbred C57BL, Mice, Transgenic, Models, Biological, Models, Genetic, Molecular Sequence Data, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Purkinje Cells, Repressor Proteins, Mice, Knockout, Spinocerebellar Ataxias, DNA Repeat Expansion, Mice, Embryonic Stem Cells
About these checks
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
