An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice.

TitleAn antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice.
Publication TypeJournal Article
Year of Publication2011
AuthorsWilburn, B, Rudnicki DD, Zhao J, Weitz TM, Cheng Y, Gu X, Greiner E, Park CS, Wang N, Sopher BL, La Spada AR, Osmand A, Margolis RL, Sun YE, Yang WX
JournalNeuron
Volume70
Issue3
Pagination427-40
Date Published2011 May 12
ISSN1097-4199
KeywordsAge Factors, Analysis of Variance, Animals, Cells, Cultured, cerebral cortex, Chromatin Immunoprecipitation, Disease Models, Animal, Embryo, Mammalian, Gene Expression Regulation, Humans, Huntington Disease, Intranuclear Inclusion Bodies, Membrane Proteins, Mice, Mice, Transgenic, Motor Activity, Neurons, Oligodeoxyribonucleotides, Antisense, Organ Size, Peptides, Time Factors, Transfection, Trinucleotide Repeat Expansion, Ubiquitin
Abstract

Huntington's disease-like-2 (HDL2) is a phenocopy of Huntington's disease caused by CTG/CAG repeat expansion at the Junctophilin-3 (JPH3) locus. The mechanisms underlying HDL2 pathogenesis remain unclear. Here we developed a BAC transgenic mouse model of HDL2 (BAC-HDL2) that exhibits progressive motor deficits, selective neurodegenerative pathology, and ubiquitin-positive nuclear inclusions (NIs). Molecular analyses reveal a promoter at the transgene locus driving the expression of a CAG repeat transcript (HDL2-CAG) from the strand antisense to JPH3, which encodes an expanded polyglutamine (polyQ) protein. Importantly, BAC-HDL2 mice, but not control BAC mice, accumulate polyQ-containing NIs in a pattern strikingly similar to those in the patients. Furthermore, BAC mice with genetic silencing of the expanded CUG transcript still express HDL2-CAG transcript and manifest polyQ pathogenesis. Finally, studies of HDL2 mice and patients revealed CBP sequestration into NIs and evidence for interference of CBP-mediated transcriptional activation. These results suggest overlapping polyQ-mediated pathogenic mechanisms in HD and HDL2.

DOI10.1111/j.1471-4159.2012.07732.x
Alternate JournalNeuron