A Long CAG Repeat in the Mouse Sca1 Locus Replicates SCA1 Features and Reveals the Impact of Protein Solubility on Selective Neurodegeneration
Open accessAbstract
To faithfully recreate the features of the human neurodegenerative disease spinocerebellar ataxia type 1 (SCA1) in the mouse, we targeted 154 CAG repeats into the endogenous mouse locus. Sca1(154Q/2Q) mice developed a progressive neurological disorder that resembles human SCA1, featuring motor incoordination, cognitive deficits, wasting, and premature death, accompanied by Purkinje cell loss and age-related hippocampal synaptic dysfunction. Mutant ataxin-1 solubility varied with brain region, being most soluble in the neurons most vulnerable to degeneration. Solubility decreased overall as the mice aged; Purkinje cells, the most affected in SCA1, did not form aggregates of mutant protein until an advanced stage of disease. It appears that those neurons that cannot sequester the mutant protein efficiently and thereby curb its toxicity suffer the worst damage from polyglutamine-induced toxicity.
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The dendritic arborization defect of Purkinje cells is the most prominent pathological sign in aging Atxn1154Q/+ animals.
“The dendritic arborization defect of the Purkinje cells in the cerebellum is the most prominent pathological sign in aging Atxn1154Q/+ animals (Watase et al., 2002; 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 Watase et al., 2002
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Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila
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Self-citationPolyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1
Lin, X., Antalffy, B., Kang, D., Orr, H. T., & Zoghbi, H. Y. (2000) · Nature Neuroscience · doi:10.1038/72101 · Cited by 374 · see citing works
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Unfolding the role of protein misfolding in neurodegenerative diseases
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Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
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Self-citationOpposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
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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
“Immunofluorescence staining of cerebellar sections and indirect quantitative analysis of Purkinje cell dendritic arborization were performed as described previously (Watase et al., 2002; Jafar-Nejad et al., 2011).”
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- Authors
- Watase, K., Weeber, E. J., Xu, B., Antalffy, B., Yuva-Paylor, L., Hashimoto, K., Kano, M., Atkinson, R., Sun, Y., Armstrong, D. L., Sweatt, J. D., Orr, H. T., Paylor, R., & Zoghbi, H. Y.
- Affiliations
- Howard Hughes Medical Institute (US)
- Kanazawa University (JP)
- University of Minnesota (US)
- Corresponding author
- Zoghbi, Huda Y.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2002-06
- Volume
- 34
- Issue
- 6
- Pages
- 905-919
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1990288633
- Cited by
- 359
- References
- 4
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 28 · 2022: 19 · 2021: 20 · 2020: 14 · 2019: 11 · 2018: 19 · 2017: 9 · 2016: 11 · 2015: 12 · 2014: 14 · 2013: 20 · 2012: 11
- FWCI
- 6.97
- 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, 4064 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)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- National Institutes of Health (NS22920, NS27699)
- National Institute of Neurological Disorders and Stroke
- Baylor College of Medicine
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- spinocerebellar ataxia type 1, CAG repeat expansion, ataxin-1, protein solubility, selective neurodegeneration, Purkinje cell degeneration, polyglutamine toxicity, cognitive impairment, motor coordination, protein aggregation
- MeSH terms
- Ataxins, Ataxin-1, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Inbred C57BL, Mice, Neurologic Mutants, Nerve Tissue Proteins, Nuclear Proteins, Purkinje Cells, Solubility, Trinucleotide Repeats, Neurodegenerative Diseases, Spinocerebellar Ataxias, Mice
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