Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release

Human Molecular Genetics
N R JanaN Nukina

Abstract

Expansion of CAG repeats within the coding region of target genes is the cause of several autosomal dominant neurodegenerative diseases including Huntington's disease (HD). A hallmark of HD is the proteolytic production of N-terminal fragments of huntingtin containing polyglutamine repeats that form ubiquitinated aggregates in the nucleus and cytoplasm of the affected neurons. In this study, we used an ecdysone-inducible stable mouse neuro2a cell line that expresses truncated N-terminal huntingtin (tNhtt) with different polyglutamine length, along with mice transgenic for HD exon 1, to demonstrate that the ubiquitin-proteasome pathway is involved in the pathogenesis of HD. Proteasomal 20S core catalytic component was redistributed to the polyglutamine aggregates in both the cellular and transgenic mouse models. Proteasome inhibitor dramatically increased the rate of aggregate formation caused by tNhtt protein with 60 glutamine (60Q) repeats, but had very little influence on aggregate formation by tNhtt protein with 150Q repeats. Both normal and polyglutamine-expanded tNhtt proteins were degraded by proteasome, but the rate of degradation was inversely proportional to the repeat length. The shift of the proteasomal components fr...Continue Reading

Citations

Jan 22, 2005·Neurotoxicity Research·Miguel Díaz-HernándezJosé J Lucas
Jun 3, 2006·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Masahiro WazaGen Sobue
Apr 11, 2013·Seminars in Immunopathology·Sang Won Park, Umut Ozcan
Feb 8, 2007·Histochemistry and Cell Biology·Jonathan Wanderer, A Jennifer Morton
Apr 25, 2007·Apoptosis : an International Journal on Programmed Cell Death·Tobias EisenbergFrank Madeo
Jul 15, 2009·Journal of Assisted Reproduction and Genetics·Yen-Chein LaiShuan-Yow Li
Mar 1, 2012·Journal of Molecular Neuroscience : MN·Xin YuAnna-Lena Ström
May 23, 2012·Molecular Neurobiology·Deepak ChhanganiAmit Mishra
May 27, 2008·Neuroscience Bulletin·Jiao-Jiao ChenZheng-Hong Qin
Apr 5, 2005·Brain Research·T NakajimaY Morita
Jun 23, 2004·Neurobiology of Disease·Andrej Michalik, Christine Van Broeckhoven
Apr 9, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Steven M Hersch, H Diana Rosas
Apr 27, 2004·Trends in Neurosciences·Félix HernándezJosé J Lucas
Mar 27, 2003·Progress in Neuro-psychopharmacology & Biological Psychiatry·Miriam A Hickey, Marie Françoise Chesselet
Jun 6, 2003·Current Opinion in Genetics & Development·Sarah J Shoesmith Berke, Henry L Paulson
Apr 4, 2003·The International Journal of Biochemistry & Cell Biology·Geoffrey M Goellner, Martin Rechsteiner
Nov 2, 2001·Trends in Molecular Medicine·R L Margolis, C A Ross
Nov 23, 2012·Cell Death & Disease·S BhutaniN R Jana
Feb 1, 2008·Nature Clinical Practice. Rheumatology·Naoko YagishitaToshihiro Nakajima
Sep 17, 2005·Nature Reviews. Molecular Cell Biology·Christopher A Ross, Michelle A Poirier
Aug 6, 2003·European Journal of Biochemistry·Alessio CardinaleSilvia Biocca
Aug 12, 2009·Proceedings of the National Academy of Sciences of the United States of America·Christa J MaynardNico P Dantuma
Jun 18, 2010·The Journal of Biological Chemistry·Rodrigo A FuentealbaRobert H Baloh
Nov 10, 2010·The Journal of Biological Chemistry·Xiang ShenBeatrice Y J T Yue
Mar 28, 2012·The Journal of Biological Chemistry·Nidhi BhutaniAlfred L Goldberg
Nov 7, 2008·The Journal of Biological Chemistry·Erwann RousseauAnne Bertolotti
Mar 13, 2009·The Journal of Biological Chemistry·Peter O BauerNobuyuki Nukina
Oct 13, 2006·Antioxidants & Redox Signaling·Mark P Mattson
Feb 3, 2006·Molecular Biology of the Cell·Alexandra BenchouaEmmanuel Brouillet
Jul 28, 2009·Cardiovascular Research·Nico P Dantuma, Kristina Lindsten
Sep 4, 2003·Human Molecular Genetics·Ben A Oostra, Rob Willemsen
Aug 8, 2009·Human Molecular Genetics·Zheng YingGuanghui Wang

❮ Previous
Next ❯

Related Concepts

Related Feeds

Apoptotic Caspases

Apoptotic caspases belong to the protease enzyme family and are known to play an essential role in inflammation and programmed cell death. Here is the latest research.

Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis