Serine 776 of Ataxin-1 Is Critical for Polyglutamine-Induced Disease in SCA1 Transgenic Mice
Open accessAbstract
Polyglutamine-induced neurodegeneration in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degradation machinery. Since phosphorylation is a prominent mechanism by which these processes are regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphorylated. Residue 776 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in tissue culture cells. The importance of S776 for polyglutamine-induced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice. These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially reduced. These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.
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S776 phosphorylation of ATXN1 is absolutely required for SCA1 pathogenesis.
“We also explored the possibility that the interaction between NLK and ATXN1 may depend on the phosphorylation status at serine 776 (S776) of ATXN1, a key feature that is absolutely required for SCA1 pathogenesis (Emamian et al., 2003; Duvick et al., 2010).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Emamian et al., 2003
No passage from our copy was returned for searches on S776 phosphorylation, disease, or ataxin-1. The paper’s title alone cannot establish that phosphorylation is absolutely required for SCA1 pathogenesis, so the claim cannot be verified from the available passages. (LLM, conf=0.69)
Experimental — accuracy not yet measuredIn SCA1, several phosphorylation sites have been identified in mouse brain in vivo including S776 and S239.
“In SCA1, several phosphorylation sites have been identified so far in mouse brain in vivo including S776 and S239 (Emamian et al., 2003; Vierra-Green et al., 2005; Huttlin et al., 2010).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Emamian et al., 2003
No passage from our copy was returned for searches on S776 or S239 phosphorylation in mouse brain, including searches for phosphorylation in vivo. The available indexed passages therefore do not establish which sites this paper identified. (LLM, conf=0.66)
Experimental — accuracy not yet measuredPhosphorylation of S776 in ATXN1 is crucial for the initiation and progression of SCA1.
“The phosphorylation of S776 in ATXN1 is extensively studied and is known to be crucial for the initiation and progression of SCA1 (Emamian et al., 2003; Duvick et al., 2010).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Emamian et al., 2003
No passage from our copy was provided or returned for searches on S776, phosphorylation, ataxin-1, and disease. Although the paper’s title concerns serine 776 and disease in SCA1 transgenic mice, the available passages do not establish what the paper says about phosphorylation or the initiation and progression of SCA1. (LLM, conf=0.65)
Experimental — accuracy not yet measured
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References 35 · Cited by 305
- Authors
- Emamian, E. S., Kaytor, M. D., Duvick, L. A., Zu, T., Tousey, S. K., Zoghbi, H. Y., Clark, H. B., & Orr, H. T.
- Affiliations
- University of Minnesota (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Orr, Harry T.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2003-05
- Volume
- 38
- Issue
- 3
- Pages
- 375-387
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W2052159338
- Cited by
- 305
- References
- 35
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 13 · 2017: 10 · 2016: 5 · 2015: 11 · 2014: 10 · 2013: 17 · 2012: 16
- FWCI
- 8.81
- 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, 3730 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
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Ataxia Foundation
- National Institute of Neurological Disorders and Stroke (NS 27699, NS-22920)
- 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 › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Keywords
- ataxin-1, phosphorylation, spinocerebellar ataxia type 1, polyglutamine expansion, neurodegeneration, Purkinje cells, intranuclear inclusions, transgenic mice, protein folding and degradation, pathogenesis
- MeSH terms
- Ataxins, Ataxin-1, Amino Acid Sequence, Animals, Cell Nucleus, Inclusion Bodies, Disease Models, Animal, Female, Cricetinae, Male, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Phenotype, Purkinje Cells, Serine, CHO Cells, COS Cells, Trinucleotide Repeat Expansion, Spinocerebellar Ataxias, Mice
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