Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 18841197.
- Also identified by DOI 10.1371/journal.pone.0003341 and PMC identifier 2553199.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Alleles
- Animals
- Ataxin-3
- Base Sequence
- Brain
- Brain/metabolism
- Cell Line
- DNA Primers
- Disease Models, Animal
- Gene Silencing
- Humans
- Machado-Joseph Disease
- Machado-Joseph Disease/genetics
- Machado-Joseph Disease/physiopathology
- Male
- Mutation
- Nerve Tissue Proteins
- Nerve Tissue Proteins/genetics
- Polymorphism, Single Nucleotide
- RNA
- RNA/genetics
- Rats
- Rats, Wistar
- Reverse Transcriptase Polymerase Chain Reaction