title: An antisense CAG repeat transcript at JPH3 locus mediates expanded polyglutamine protein toxicity in Huntington's disease-like 2 mice.
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.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Center for Neurobehavioral Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Wilburn
authors.forename: Dobrila D
authors.initials: DD
authors.lastname: Rudnicki
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.forename: Tara Murphy
authors.initials: TM
authors.lastname: Weitz
authors.forename: Yin
authors.initials: Y
authors.lastname: Cheng
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Gu
authors.forename: Erin
authors.initials: E
authors.lastname: Greiner
authors.forename: Chang Sin
authors.initials: CS
authors.lastname: Park
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Bryce L
authors.initials: BL
authors.lastname: Sopher
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.forename: Alex
authors.initials: A
authors.lastname: Osmand
authors.forename: Russell L
authors.initials: RL
authors.lastname: Margolis
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.forename: X William
authors.initials: XW
authors.lastname: Yang
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D020319:Oligodeoxyribonucleotides, Antisense / Q000378:metabolism*; D009929:Organ Size / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D010455:Peptides; D025801:Ubiquitin; C412507:junctophilin; C097188:polyglutamine