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Title: Suppression of somatic expansion delays the onset of pathophysiology in a mouse model of Huntington’s Disease

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.
 [1] ;  [2] ;  [1] ;  [3] ;  [1] ;  [4] ;  [5] ;  [6] ;  [6] ;  [1] ;  [7]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Life Sciences Division.
  2. Mayo Clinic, Rochester, MN (United States). Dept. of Molecular Pharmacology and Experimental Therapeutics.
  3. Kookmin University, Seoul (Korea). Department of Bio and Fermentation Convergence Technology.
  4. Univ. of Oslo, Oslo (Norway). Dept. of Neuropathology; Univ. of Lubeck, Lubeck (Germany). LIED.
  5. The Univ. of Texas Medical Branch, Galveston, TX (United States). Dept. of Anestesiology.
  6. Univ. of Puerto Rico, San Juan (Puerto Rico). Puerto Rico Center for Inherited Diseases and Dept. of Pharmacology and Toxicology.
  7. St Jude Children's Research Hospital, Memphis, TN (United States)
Publication Date:
Grant/Contract Number:
Accepted Manuscript
Journal Name:
PLoS Genetics
Additional Journal Information:
Journal Volume: 11; Journal Issue: 8; Journal ID: ISSN 1553-7404
Public Library of Science
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
USDOE; National Institutes of Health (NIH)
Country of Publication:
United States
59 BASIC BIOLOGICAL SCIENCES; animal performance; Huntington disease; toxicity; age groups; neostriatum; alleles; pathology and laboratory medicine; mouse models
OSTI Identifier: