Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease

PLoS One. 2008 Oct 8;3(10):e3341. doi: 10.1371/journal.pone.0003341.


Recent studies have demonstrated that RNAi is a promising approach for treating autosomal dominant disorders. However, discrimination between wild-type and mutant transcripts is essential, to preserve wild-type expression and function. A single nucleotide polymorphism (SNP) is present in more than 70% of patients with Machado-Joseph disease (MJD). We investigated whether this SNP could be used to inactivate mutant ataxin-3 selectively. Lentiviral-mediated silencing of mutant human ataxin-3 was demonstrated in vitro and in a rat model of MJD in vivo. The allele-specific silencing of ataxin-3 significantly decreased the severity of the neuropathological abnormalities associated with MJD. These data demonstrate that RNAi has potential for use in MJD treatment and constitute the first proof-of-principle for allele-specific silencing in the central nervous system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Animals
  • Ataxin-3
  • Base Sequence
  • Brain / metabolism
  • Cell Line
  • DNA Primers
  • Disease Models, Animal*
  • Gene Silencing*
  • Humans
  • Machado-Joseph Disease / genetics*
  • Machado-Joseph Disease / physiopathology
  • Male
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • RNA / genetics*
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction


  • DNA Primers
  • Nerve Tissue Proteins
  • RNA
  • Ataxin-3
  • Atxn3 protein, rat