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Putting the Brakes on Huntington Disease in a Mouse Experimental Model
- Source :
- PLoS Genetics, Vol 11, Iss 8, p e1005409 (2015), PLoS Genetics
- Publication Year :
- 2015
- Publisher :
- Public Library of Science (PLoS), 2015.
-
Abstract
- Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. We have created an HD mouse model that resolves the effects of the inherited and somatic expansions. We show here that suppressing somatic expansion substantially delays the onset of disease in littermates that inherit the same disease-length allele. Furthermore, a pharmacological inhibitor, XJB-5-131, inhibits the lengthening of the repeat tracks, and correlates with rescue of motor decline in these animals. The results provide evidence that pharmacological approaches to offset disease progression are possible.<br />Author Summary Huntington’s Disease (HD) is caused by inheritance of a single disease-length allele harboring an expanded CAG repeat, which continues to expand in somatic tissues with age. There is no correction for the inherited mutation, but if somatic expansion contributes to disease, then a therapeutic approach is possible. The inherited disease allele expresses a toxic protein, and whether further somatic expansion adds to toxicity is unknown. Here we describe a mouse model of Huntington’s disease that allows us to separate out the effects of the inherited gene from the expansion that occurs during life. We find that blocking the continued expansion of the gene causes a delay in onset of symptoms. This result opens the doors to future therapeutics designed to shorten the repeat.
- Subjects :
- Male
congenital, hereditary, and neonatal diseases and abnormalities
Cancer Research
lcsh:QH426-470
Neural degeneration
Disease
Biology
Cyclic N-Oxides
03 medical and health sciences
Exon
0302 clinical medicine
Mutant protein
mental disorders
Genetics
Animals
Hereditary Neurodegenerative Disorder
Molecular Biology
Genetics (clinical)
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
0303 health sciences
Polyglutamine tract
lcsh:Genetics
Huntington Disease
Female
Age of onset
Trinucleotide Repeat Expansion
Trinucleotide repeat expansion
030217 neurology & neurosurgery
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 11
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....f4ed1959d904f037a26920f776aa3d62