Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1
Open accessAbstract
Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a glutamine-encoding repeat in ataxin 1 (ATXN1). In all known polyglutamine diseases, the glutamine expansion confers toxic functions onto the protein; however, the mechanism by which this occurs remains enigmatic, in light of the fact that the mutant protein apparently maintains interactions with its usual partners. Here we show that the expanded polyglutamine tract differentially affects the function of the host protein in the context of different endogenous protein complexes. Polyglutamine expansion in ATXN1 favours the formation of a particular protein complex containing RBM17, contributing to SCA1 neuropathology by means of a gain-of-function mechanism. Concomitantly, polyglutamine expansion attenuates the formation and function of another protein complex containing ATXN1 and capicua, contributing to SCA1 through a partial loss-of-function mechanism. This model provides mechanistic insight into the molecular pathogenesis of SCA1 as well as other polyglutamine diseases.
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Neurodegeneration in SCA1 results from a gain of endogenous functions mediated by polyglutamine-expanded mutant ATXN1 and from a concurrent partial loss of the beneficial functions of wild-type ATXN1.
“in SCA1 results from a gain of endogenous functions mediated by the polyglutamine-expanded mutant ATXN1, and from a concurrent partial loss of the beneficial functions of wild-type ATXN1 (Lim et al., 2008; 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 Lim et al., 2008
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 Lim et al., 2008
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 Lim et al., 2008
Interactors in that network were potential modifiers of disease progression, and subsequent work found that gain of function mediated by a newly identified protein complex mediates disease pathogenesis.
“Importantly, interactors in the network were potential modifiers of disease progression, and, in subsequent work, gain of function mediated by a newly identified protein complex was found to mediate disease pathogenesis165.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [165]
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Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1
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“Gel-filtration (sizing) chromatography was performed as described previously with slight modifications (Lam et al., 2006; Lim et al., 2008).”
InfluentialSelf-citation
- Authors
- Lim, J., Crespo-Barreto, J., Jafar-Nejad, P., Bowman, A. B., Richman, R., Hill, D. E., Orr, H. T., & Zoghbi, H. Y.
- Affiliations
- Baylor College of Medicine (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- University of Minnesota (US)
- Corresponding author
- Zoghbi, Huda Y.
- Venue
- Nature
- Published
- 2008-03-12
- Volume
- 452
- Issue
- 7188
- Pages
- 713-718
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2377396
- OpenAlex
- W2008526580
- Cited by
- 311
- References
- 43
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 6 · 2023: 8 · 2022: 6 · 2021: 10 · 2020: 15 · 2019: 11 · 2018: 17 · 2017: 15 · 2016: 13 · 2015: 21 · 2014: 14 · 2013: 34 · 2012: 29
- FWCI
- 14.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Neurological Disorders and Stroke (R01NS027699)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (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 › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Keywords
- spinocerebellar ataxia type 1, polyglutamine expansion, ataxin-1, Capicua, protein complexes, gain-of-function toxicity, neurodegeneration, molecular pathogenesis, protein-protein interaction
- MeSH terms
- Ataxins, Ataxin-1, RNA Splicing Factors, Alleles, Animals, Drosophila melanogaster, Humans, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Protein Binding, Purkinje Cells, Repressor Proteins, Open Reading Frames, RNA-Binding Proteins, Ribonucleoprotein, U2 Small Nuclear, Trinucleotide Repeat Expansion, Spinocerebellar Ataxias, Two-Hybrid System Techniques, Protein Structure, Quaternary, Drosophila Proteins, Multiprotein Complexes, Mice
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