An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice

Brian Wilburn, Dobrila D. Rudnicki, Jing Zhao, Tara Murphy Weitz, Yin Cheng, Xiaofeng Gu, Erin Greiner, Chang Sin Park, Nan Wang, Bryce L. Sopher, Albert R. La Spada, Alex Osmand, Russell L. Margolis, Yi E. Sun, X. William Yang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)427-440
Number of pages14
JournalNeuron
Volume70
Issue number3
DOIs
StatePublished - May 12 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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