Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease

Helen Budworth, Faye R. Harris, Paul Williams, Do Yup Lee, Amy Holt, Jens Pahnke, Bartosz Szczesny, Karina Acevedo-Torres, Sylvette Ayala-Peña, Cynthia T. McMurray

Research output: Contribution to journalArticle

44 Scopus citations

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.

Original languageEnglish (US)
Article numbere1005267
JournalPLoS genetics
Volume11
Issue number8
DOIs
StatePublished - Aug 1 2015

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    Budworth, H., Harris, F. R., Williams, P., Lee, D. Y., Holt, A., Pahnke, J., Szczesny, B., Acevedo-Torres, K., Ayala-Peña, S., & McMurray, C. T. (2015). Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington’s Disease. PLoS genetics, 11(8), [e1005267]. https://doi.org/10.1371/journal.pgen.1005267