Abstract
Polyglutamine expansion in huntingtin (Htt) and the androgen receptor (AR) causes untreatable neurodegenerative diseases. Y-27632, a therapeutic lead, reduces Htt and AR aggregation in cultured cells, and Htt-induced neurodegeneration in Drosophila. Y-27632 inhibits both Rho-associated kinases ROCK and PRK-2, making its precise intracellular target uncertain. Over-expression of either kinase increases Htt and AR aggregation. Three ROCK inhibitors (Y-27632, HA-1077, and H-1152P), and a specific ROCK inhibitory peptide reduce polyglutamine protein aggregation, as does knockdown of ROCK or PRK-2 by RNAi. RNAi also indicates that each kinase is required for the inhibitory effects of Y-27632 to manifest fully. These two actin regulatory kinases are thus involved in polyglutamine aggregation, and their simultaneous inhibition may be an important therapeutic goal.
References
Jul 4, 1991·Nature·A R La SpadaK H Fischbeck
Aug 26, 1996·FEBS Letters·O NakagawaS Narumiya
Oct 1, 1996·Molecular and Cellular Biology·T LeungL Lim
Mar 10, 1997·FEBS Letters·T IshizakiS Narumiya
Apr 1, 1997·Molecular and Cellular Biology·S Vincent, J Settleman
Feb 28, 1998·The Journal of Biological Chemistry·H KatohM Negishi
Jul 1, 1998·The Journal of Cell Biology·M HiroseS Narumiya
Mar 11, 1999·Acta neurochirurgica·E TachibanaJ Yoshida
Nov 5, 1999·The Journal of Biological Chemistry·M AmanoK Kaibuchi
May 20, 2000·The Journal of Biological Chemistry·N ArimuraK Kaibuchi
Jun 6, 2000·Neuron·H BitoS Narumiya
Jul 6, 2000·Journal of Neurosurgery·M HaraJ Yoshida
Nov 18, 2000·Experimental Cell Research·M AmanoK Kaibuchi
Feb 13, 2001·Trends in Pharmacological Sciences·Y FukataK Kaibuchi
Jun 18, 2002·Journal of Neurochemistry·Mami IkenoyaYasuharu Sasaki
Aug 23, 2002·Pharmacology & Therapeutics·Yasuharu SasakiHiroyoshi Hidaka
Oct 24, 2002·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Nina Wettschureck, Stefan Offermanns
May 23, 2003·Journal of Biochemistry·Hideyuki Mukai
Jun 5, 2003·Nature Reviews. Molecular Cell Biology·Kirsi Riento, Anne J Ridley
Nov 15, 2003·Science·Yan ZhouBinhui Ni
Nov 19, 2003·Neuron·Sonia K PollittMarc I Diamond
Jun 29, 2004·Neuroscience·H TanakaM Tohyama
May 3, 2005·Nature Reviews. Drug Discovery·Bernhard K MuellerNicole Teusch
May 25, 2006·Human Molecular Genetics·Urvee A DesaiMarc I Diamond
Mar 8, 2007·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Anatoli B MeriinMichael Y Sherman
Nov 17, 2007·Nature Chemical Biology·William A WeissKevan M Shokat
Citations
May 24, 2013·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Barbara CalaminiLinda S Kaltenbach
Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Brandon B HolmesMarc I Diamond
Jan 16, 2013·The Journal of Biological Chemistry·Zhiqiang ZhengMarc I Diamond
Mar 13, 2009·The Journal of Biological Chemistry·Peter O BauerNobuyuki Nukina
Jun 25, 2008·Molecular and Cellular Biology·Jieya ShaoMarc I Diamond
Aug 30, 2012·Molecular Neurodegeneration·Peter O BauerNobuyuki Nukina
Dec 18, 2009·PloS One·Carole DeytsSandrine Bétuing
Feb 9, 2010·PloS One·Suzanne AngeliMarc I Diamond
Apr 8, 2014·Human Molecular Genetics·Stefanie L ButlandMichael R Hayden
Aug 17, 2010·Pharmacology & Therapeutics·Megan J DowieMichelle Glass
Jan 3, 2016·Drug Discovery Today. Technologies·Olivier Defert, Sandro Boland
Jul 14, 2009·Neurobiology of Disease·Mei LiMarc I Diamond
Jul 17, 2012·Neuron·Dyna I ShirasakiX William Yang
Jun 5, 2015·Cellular Microbiology·Jyoti Prasad MishraMarkus Stein
Oct 12, 2016·Journal of Smooth Muscle Research = Nihon Heikatsukin Gakkai Kikanshi·Simon Lin, Frank V Brozovich
Nov 22, 2016·Medicinal Research Reviews·Sofia EstevesPatrícia Maciel
Jun 29, 2010·Journal of Biomolecular Screening·Linda S KaltenbachDonald C Lo
Jan 11, 2014·The Journal of Biological Chemistry·Cendrine TouretteRobert E Hughes
Feb 21, 2019·Scientific Reports·Sabine KleinJonel Trebicka
Mar 31, 2012·The Journal of Biological Chemistry·Najla KfouryMarc I Diamond
Jun 15, 2019·Annals of the New York Academy of Sciences·Jennifer CableNicolas L Fawzi
Mar 22, 2020·Journal of Clinical Medicine·Kyeongseok KimSsang-Goo Cho
Dec 2, 2020·Nanomedicine : Nanotechnology, Biology, and Medicine·Christian MacksJeoung Soo Lee
Jul 9, 2021·Frontiers in Cell and Developmental Biology·Faliang WangJieya Shao