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PLoS Genet. 2015 Aug 6;11(8):e1005267. doi: 10.1371/journal.pgen.1005267. eCollection 2015 Aug.

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

Author information

1
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
2
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
3
Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, Korea.
4
Department of Neuropathology, University of Oslo, Oslo, Norway; LIED, University of Lübeck, Lübeck, Germany.
5
Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
6
Puerto Rico Center for Inherited Diseases, University of Puerto Rico, San Juan, Puerto Rico; Department of Pharmacology and Toxicology, University of Puerto Rico, San Juan, Puerto Rico.

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.

PMID:
26247199
PMCID:
PMC4527696
DOI:
10.1371/journal.pgen.1005267
[Indexed for MEDLINE]
Free PMC Article

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