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 progr...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2011-05, Vol.70 (3), p.427-440
Main Authors: Wilburn, Brian, Rudnicki, Dobrila D., Zhao, Jing, Weitz, Tara Murphy, Cheng, Yin, Gu, Xiaofeng, Greiner, Erin, Park, Chang Sin, Wang, Nan, Sopher, Bryce L., La Spada, Albert R., Osmand, Alex, Margolis, Russell L., Sun, Yi E., Yang, X. William
Format: Article
Language:English
Subjects:
Age Factors
Analysis of Variance
Animals
Artificial chromosomes
Brain
Cells, Cultured
Cerebral Cortex - cytology
Chromatin Immunoprecipitation - methods
Disease Models, Animal
Embryo, Mammalian
Gene Expression Regulation - genetics
Humans
Huntington Disease - drug therapy
Huntington Disease - genetics
Huntington Disease - physiopathology
Huntingtons disease
Intranuclear Inclusion Bodies - metabolism
Intranuclear Inclusion Bodies - pathology
Membrane Proteins - genetics
Methods
Mice
Mice, Transgenic
Motor Activity - genetics
Neurodegeneration
Neurons - metabolism
Neurosciences
Oligodeoxyribonucleotides, Antisense - metabolism
Organ Size - genetics
Peptides - genetics
Peptides - toxicity
Proteins
Rodents
Time Factors
Toxicity
Transfection
Trinucleotide Repeat Expansion - genetics
Ubiquitin - metabolism
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Summary: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. ► An expanded CAG transcript mediates polyglutamine toxicity in HDL2 mice ► HDL2 mice with genetic silencing of CUG transcripts still manifest polyQ toxicity ► HDL2 and HD may share overlapping mechanisms in polyQ-mediated CBP interference
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2011.03.021