An Antisense CAG Repeat Transcript at JPH3 Locus Mediates Expanded Polyglutamine Protein Toxicity in Huntington's Disease-like 2 Mice
Copyright policy )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.
- JOHNS HOPKINS UNIVERSITY
- University of California, San Diego United States
- Johns Hopkins University Sch of Medicine United States
- University of California, Los Angeles United States
- Johns Hopkins University School of Medicine United States
Cerebral Cortex, Neurons, Analysis of Variance, Chromatin Immunoprecipitation, Neuroscience(all), Intranuclear Inclusion Bodies, Age Factors, Membrane Proteins, Mice, Transgenic, Organ Size, Motor Activity, Embryo, Mammalian, Oligodeoxyribonucleotides, Antisense, Disease Models, Animal, Mice, Huntington Disease, Gene Expression Regulation, Animals, Humans, Peptides, Cells, Cultured
Cerebral Cortex, Neurons, Analysis of Variance, Chromatin Immunoprecipitation, Neuroscience(all), Intranuclear Inclusion Bodies, Age Factors, Membrane Proteins, Mice, Transgenic, Organ Size, Motor Activity, Embryo, Mammalian, Oligodeoxyribonucleotides, Antisense, Disease Models, Animal, Mice, Huntington Disease, Gene Expression Regulation, Animals, Humans, Peptides, Cells, Cultured
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