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

Nature. 2008 Jun 19;453(7198):1107-11. doi: 10.1038/nature06909. Epub 2008 Apr 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Ataxin-3
  • Disease Models, Animal
  • Drosophila / genetics
  • Drosophila / metabolism*
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Eye / metabolism
  • Eye / pathology
  • Humans
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Nerve Degeneration*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Peptides / genetics*
  • Peptides / metabolism
  • Peptides / toxicity
  • RNA / genetics
  • RNA / toxicity*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Trinucleotide Repeat Expansion / genetics
  • Up-Regulation


  • Drosophila Proteins
  • MBNL1 protein, human
  • Mutant Proteins
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • RNA-Binding Proteins
  • Repressor Proteins
  • mbl protein, Drosophila
  • polyglutamine
  • RNA
  • ATXN3 protein, human
  • Ataxin-3