title: Suppression of Somatic Expansion Delays the Onset of Pathophysiology in a Mouse Model of Huntington's Disease.
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.
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Helen
authors.initials: H
authors.lastname: Budworth
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Faye R
authors.initials: FR
authors.lastname: Harris
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Williams
authors.affiliation: Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul, Korea.
authors.forename: Do Yup
authors.initials: DY
authors.lastname: Lee
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Amy
authors.initials: A
authors.lastname: Holt
authors.affiliation: Department of Neuropathology, University of Oslo, Oslo, Norway; LIED, University of Lübeck, Lübeck, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.affiliation: Department of Anesthesiology, The University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Szczesny
authors.affiliation: 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.
authors.forename: Karina
authors.initials: K
authors.lastname: Acevedo-Torres
authors.affiliation: 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.
authors.forename: Sylvette
authors.initials: S
authors.lastname: Ayala-Peña
authors.affiliation: Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, United States of America.
authors.forename: Cynthia T
authors.initials: CT
authors.lastname: McMurray
mesh_terms: D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D045647:DNA Glycosylases / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019680:Trinucleotide Repeat Expansion / Q000187:drug effects*
chemical_list: D003497:Cyclic N-Oxides; C523959:XJB-5-131; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse