Expanded ATXN3 frameshifting events are toxic in Drosophila and mammalian neuron models

Hum Mol Genet. 2012 May 15;21(10):2211-8. doi: 10.1093/hmg/dds036. Epub 2012 Feb 14.


Spinocerebellar ataxia type 3 is caused by the expansion of the coding CAG repeat in the ATXN3 gene. Interestingly, a -1 bp frameshift occurring within an (exp)CAG repeat would henceforth lead to translation from a GCA frame, generating polyalanine stretches instead of polyglutamine. Our results show that transgenic expression of (exp)CAG ATXN3 led to -1 frameshifting events, which have deleterious effects in Drosophila and mammalian neurons. Conversely, transgenic expression of polyglutamine-encoding (exp)CAA ATXN3 was not toxic. Furthermore, (exp)CAG ATXN3 mRNA does not contribute per se to the toxicity observed in our models. Our observations indicate that expanded polyglutamine tracts in Drosophila and mouse neurons are insufficient for the development of a phenotype. Hence, we propose that -1 ribosomal frameshifting contributes to the toxicity associated with (exp)CAG repeats.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Ataxin-3
  • Drosophila / genetics*
  • Drosophila / metabolism
  • Frameshifting, Ribosomal*
  • Immunohistochemistry
  • Machado-Joseph Disease / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Neurons / metabolism*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Peptides / chemistry
  • RNA, Messenger / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transfection
  • Trinucleotide Repeat Expansion


  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Peptides
  • RNA, Messenger
  • Transcription Factors
  • polyalanine
  • Ataxin-3
  • Atxn3 protein, mouse