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Cited by 136Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersAmyotrophic Lateral Sclerosis Research

Partial Loss of Ataxin-1 Function Contributes to Transcriptional Dysregulation in Spinocerebellar Ataxia Type 1 Pathogenesis

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Crespo-Barreto, Juan, Fryer, John D., Shaw, Chad A., Orr, Harry T., Zoghbi, Huda Y.·2010·PLoS Genetics
DOI 10.1371/journal.pgen.1001021PMC PMC2900305
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Abstract

Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by expansion of a CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1). Molecular and genetic data indicate that SCA1 is mainly caused by a gain-of-function mechanism. However, deletion of wild-type ATXN1 enhances SCA1 pathogenesis, whereas increased levels of an evolutionarily conserved paralog of ATXN1, Ataxin 1-Like, ameliorate it. These data suggest that a partial loss of ATXN1 function contributes to SCA1. To address this possibility, we set out to determine if the SCA1 disease model (Atxn1(154Q/+) mice) and the loss of Atxn1 function model (Atxn1-/- mice) share molecular changes that could potentially contribute to SCA1 pathogenesis. To identify transcriptional changes that might result from loss of function of ATXN1 in SCA1, we performed gene expression microarray studies on cerebellar RNA from Atxn1-/- and Atxn1(154Q/+) cerebella and uncovered shared gene expression changes. We further show that mild overexpression of Ataxin-1-Like rescues several of the molecular and behavioral defects in Atxn1-/- mice. These results support a model in which Ataxin 1-Like overexpression represses SCA1 pathogenesis by compensating for a partial loss of function of Atxn1. Altogether, these data provide evidence that partial loss of Atxn1 function contributes to SCA1 pathogenesis and raise the possibility that loss-of-function mechanisms contribute to other dominantly inherited neurodegenerative 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 Crespo-Barreto et al., 2010

  • 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 Crespo-Barreto et al., 2010

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Authors
Crespo-Barreto, J., Fryer, J. D., Shaw, C. A., Orr, H. T., & Zoghbi, H. Y.
Affiliations
  • Baylor College of Medicine (US)
  • University of Minnesota (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Zoghbi, Huda Y.
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2010-07-08
Volume
6
Issue
7
Pages
e1001021
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1001021
PMC
PMC2900305
OpenAlex
W2143856195
Cited by
136
References
56
Citations by year
2026: 6 · 2025: 6 · 2024: 5 · 2023: 6 · 2022: 9 · 2021: 6 · 2020: 9 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 8 · 2015: 6 · 2014: 10 · 2013: 15 · 2012: 12
FWCI
4.40
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health (5f31ns052925-02, NS27699, NS22920)
  • Intellectual and Developmental Disabilities Research Center (P30HD024064)
  • National Institute of Neurological Disorders and Stroke (R37NS022920, NS 27699, T32NS043124, NS45667, NS-22920, R01NS022920, 1F31NS052925, F31 NS052925, R01NS045667, R37NS027699, 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
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
spinocerebellar ataxia type 1, transcriptional dysregulation, CAG repeat expansion, polyglutamine, gain-of-function mechanism, loss-of-function mechanism, neurodegenerative diseases
MeSH terms
Ataxins, Ataxin-1, Animals, Cerebellum, Gene Expression Regulation, Nerve Tissue Proteins, Nuclear Proteins, RNA, Messenger, Transcription, Genetic, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Spinocerebellar Ataxias, Gene Expression Profiling, Mice

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