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Cited by 316Genetic Neurodegenerative DiseasesGenetics and Neurodevelopmental DisordersAmyotrophic Lateral Sclerosis Research

RNA toxicity is a component of ataxin-3 degeneration in Drosophila

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Li, Ling-Bo, Yu, Zhenming, Teng, Xiuyin, Bonini, Nancy M.·2008·Nature
DOI 10.1038/nature06909PMC PMC2574630
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Abstract

Polyglutamine (polyQ) diseases are a class of dominantly inherited neurodegenerative disorders caused by the expansion of a CAG repeat encoding glutamine within the coding region of the respective genes. The molecular and cellular pathways underlying polyQ-induced neurodegeneration are the focus of much research, and it is widely considered that toxic activities of the protein, resulting from the abnormally long polyQ tract, cause pathogenesis. Here we provide evidence for a pathogenic role of the CAG repeat RNA in polyQ toxicity using Drosophila. In a Drosophila screen for modifiers of polyQ degeneration induced by the spinocerebellar ataxia type 3 (SCA3) protein ataxin-3, we isolated an upregulation allele of muscleblind (mbl), a gene implicated in the RNA toxicity of CUG expansion diseases. Further analysis indicated that there may be a toxic role of the RNA in polyQ-induced degeneration. We tested the role of the RNA by altering the CAG repeat sequence to an interrupted CAACAG repeat within the polyQ-encoding region; this dramatically mitigated toxicity. In addition, expression of an untranslated CAG repeat of pathogenic length conferred neuronal degeneration. These studies reveal a role for the RNA in polyQ toxicity, highlighting common components in RNA-based and polyQ-protein-based trinucleotide repeat expansion diseases.

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Cited by

Sorted by citations

Authors
Li, L.-B., Yu, Z., Teng, X., & Bonini, N. M.
Affiliations
Howard Hughes Medical Institute (US)
Corresponding author
Bonini, Nancy M.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2008-04-30
Volume
453
Issue
7198
Pages
1107-1111
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature06909
PMC
PMC2574630
OpenAlex
W2083076780
Cited by
316
References
0
Citations by year
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FWCI
12.98
Type
journal article
Language
en
Open access
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 (R01NS043578)
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
RNA toxicity, ataxin-3, polyglutamine diseases, spinocerebellar ataxia type 3, CAG repeat expansion, Drosophila, modifier screen, neurodegeneration, myotonic dystrophy, fragile X syndrome
MeSH terms
Ataxin-3, Animals, Disease Models, Animal, Drosophila, Eye, Humans, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Peptides, Repressor Proteins, RNA, Up-Regulation, RNA-Binding Proteins, Trinucleotide Repeat Expansion, Drosophila Proteins, Mutant Proteins

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