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

Neuron
Brian WilburnX William Yang

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.

References

Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·A KazantsevD Housman
May 24, 2000·Proceedings of the National Academy of Sciences of the United States of America·J S SteffanL M Thompson
Aug 25, 2000·Human Molecular Genetics·A McCampbellK H Fischbeck
Apr 12, 2001·BMC Developmental Biology·S SrinivasF Costantini
Oct 9, 2001·Human Molecular Genetics·A MankodiC A Thornton
Mar 22, 2002·Biochemical and Biophysical Research Communications·Miyuki NishiHiroshi Takeshima
Apr 25, 2002·Human Molecular Genetics·Zhao-Xue YuXiao-Jiang Li
Jun 5, 2002·Human Molecular Genetics·Josephine C DorsmanGert-Jan B van Ommen
Aug 15, 2002·Trends in Genetics : TIG·Huda Y Zoghbi, Juan Botas
Dec 13, 2003·Science·Rahul N KanadiaMaurice S Swanson
Oct 7, 2004·Annals of Neurology·Russell L MargolisPenny Greenstein
Sep 6, 2005·Science·S KatayamaUNKNOWN FANTOM Consortium
May 24, 2006·Human Molecular Genetics·Xiaoyan LinCharles A Thornton
Jun 17, 2006·Annual Review of Neuroscience·Laura P W Ranum, Thomas A Cooper
Oct 19, 2006·Methods in Enzymology·Alexander P OsmandRonald Wetzel
Mar 3, 2007·Seminars in Pediatric Neurology·Richard E Lutz
Mar 28, 2007·Annals of Neurology·Dobrila D RudnickiRussell L Margolis
Apr 10, 2007·Annual Review of Neuroscience·Harry T Orr, Huda Y Zoghbi
May 23, 2007·Movement Disorders : Official Journal of the Movement Disorder Society·Penny E GreensteinJeffrey T Joseph
Sep 7, 2007·Nature Clinical Practice. Neurology·Susanne A SchneiderKailash P Bhatia
Apr 2, 2008·Journal of Neuropathology and Experimental Neurology·Dobrila D RudnickiRussell L Margolis
Jun 14, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Michelle GrayX William Yang
Jul 29, 2010·Physiological Reviews·Chiara ZuccatoElena Cattaneo

❮ Previous
Next ❯

Citations

Feb 20, 2013·Journal of Molecular Neuroscience : MN·Anna Rocchi, Maria Pennuto
Sep 6, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Anne SchneiderAnne-Laurence Boutillier
Aug 3, 2013·Cell Death & Disease·R NalavadeS Krauss
Aug 8, 2012·Nature Medicine·Mira Jakovcevski, Schahram Akbarian
Jul 7, 2011·Human Molecular Genetics·Marzena Wojciechowska, Wlodzimierz J Krzyzosiak
Sep 13, 2011·Nucleic Acids Research·Wlodzimierz J KrzyzosiakPiotr Kozlowski
Nov 20, 2013·International Journal of Molecular Sciences·Edward C Lauterbach
Jan 8, 2014·Acta Neuropathologica·Tania F GendronLeonard Petrucelli
Nov 20, 2013·Proceedings of the National Academy of Sciences of the United States of America·Tao ZuLaura P W Ranum
Sep 11, 2014·Neural Regeneration Research·Mingxia YuJiancheng Tu
Mar 15, 2014·Current Opinion in Hematology·Lucia De FranceschiNarla Mohandas
Mar 19, 2014·Trends in Molecular Medicine·Andrew P LandstromXander H T Wehrens
Apr 25, 2013·The Journal of Biological Chemistry·Judith GillisEric A Reits
Sep 5, 2015·Movement Disorders : Official Journal of the Movement Disorder Society·Elizabeth E O'HearnRussell L Margolis
Dec 12, 2012·Trends in Cell Biology·Elyse S BlumShai Shaham
Oct 16, 2012·Progress in Neurobiology·Rory JohnsonNoel J Buckley
Mar 20, 2012·Neurobiology of Disease·Rainer ProhaskaRuth H Walker
Feb 7, 2012·Journal of Molecular Biology·Ronald Wetzel
Dec 9, 2014·RNA Biology·Martyna O UrbanekWlodzimierz J Krzyzosiak
Dec 13, 2012·BioFactors·Urszula PolakMarek Napierala
Mar 1, 2012·Annals of Neurology·Ana I SeixasDobrila D Rudnicki
Apr 11, 2014·American Journal of Medical Genetics. Part a·Andrea H SeeleyDonna M Martin
Oct 2, 2014·Journal of Genetics and Genomics = Yi Chuan Xue Bao·Ranhui DuanPeng Jin
May 15, 2013·DNA Repair·Helen Budworth, Cynthia T McMurray
Jun 17, 2015·American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics : the Official Publication of the International Society of Psychiatric Genetics·Amanda KrauseRussell Margolis
Aug 15, 2015·BMC Genomics·Troy A HackettKaroly Mirnics
May 7, 2013·Biochimica Et Biophysica Acta·Kathleen A BurkeJustin Legleiter
Dec 3, 2013·Journal of Molecular Biology·Karunakar KarRonald Wetzel
Aug 12, 2014·Biochemical Society Transactions·Matthias GrohNatalia Gromak
Sep 21, 2011·Progress in Neurobiology·Maria Jimenez-SanchezDavid C Rubinsztein
Nov 15, 2011·Progress in Neurobiology·Abigail J Renoux, Peter K Todd
Feb 9, 2012·Experimental Neurology·Huiping TanPeng Jin
May 11, 2011·Neuron·Harry T Orr
Jan 3, 2013·Molecular and Cellular Neurosciences·Veronique V BelzilLeonard Petrucelli

❮ Previous
Next ❯

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