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


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.

Pubmed ID: 21555070


  • Wilburn 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 XW



Publication Data

May 12, 2011

Associated Grants

  • Agency: NIMH NIH HHS, Id: 5T32MH073526
  • Agency: NINDS NIH HHS, Id: R01 NS049501
  • Agency: NINDS NIH HHS, Id: R01 NS049501-01
  • Agency: NINDS NIH HHS, Id: R01 NS049501-02
  • Agency: NINDS NIH HHS, Id: R01 NS049501-03
  • Agency: NINDS NIH HHS, Id: R01 NS049501-04
  • Agency: NINDS NIH HHS, Id: R01 NS049501-05
  • Agency: NINDS NIH HHS, Id: R01 NS064138
  • Agency: NINDS NIH HHS, Id: R01NS049501
  • Agency: NINDS NIH HHS, Id: R01NS064138
  • Agency: NINDS NIH HHS, Id: R21NS057516

Mesh Terms

  • Age 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