@article{da05d020f5cd43b3bdef200532e75877,
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.",
author = "Brian Wilburn and Rudnicki, {Dobrila D.} and Jing Zhao and Weitz, {Tara Murphy} and Yin Cheng and Xiaofeng Gu and Erin Greiner and Park, {Chang Sin} and Nan Wang and Sopher, {Bryce L.} and {La Spada}, {Albert R.} and Alex Osmand and Margolis, {Russell L.} and Sun, {Yi E.} and Yang, {X. William}",
note = "Funding Information: This work was generously supported by independent research grants from the Hereditary Disease Foundation to X.W.Y., R.L.M., A.O., and to D.D.R. X.W.Y. is also supported by National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS; R01NS049501), the David Weil Fund to the Semel Institute at University of California, Los Angeles, and Neuroscience of Brain Disorders Award from The McKnight Endowment Fund for Neuroscience. R.L.M. and D.D.R. are supported by NIH/NINDS (R21NS057516 and R01NS064138). We would like to thank N.S. Wexler and C. Johnson for their tremendous support of this project. We also thank members of the Yang lab for discussions and reading of the manuscript. B.W. and C.S.P. were supported by predoctoral fellowships from the UCLA Center for Neurobehavioral Genetics Predoctoral Training Program funded by National Institute of Mental Health (5T32MH073526). ",
year = "2011",
month = may,
day = "12",
doi = "10.1016/j.neuron.2011.03.021",
language = "English (US)",
volume = "70",
pages = "427--440",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "3",
}