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

Abstract

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.

• Authors: Sandro Alves, Isabel Nascimento-Ferreira, Gwennaëlle Auregan, Raymonde Hassig, Noëlle Dufour, Emmanuel Brouillet, Maria C Pedroso de Lima, Philippe Hantraye, Luís Pereira de Almeida, Nicole Déglon
• Journal: PloS one (PLoS One) Vol. 3 Issue 10 Pg. e3341 (Oct 08 2008) ISSN: 1932-6203 [Electronic] United States
• PMID: 18841197 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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