ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation.

FEBS Letters
Jieya ShaoMarc I Diamond

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

Feb 28, 1998·The Journal of Biological Chemistry·H KatohM Negishi
Nov 5, 1999·The Journal of Biological Chemistry·M AmanoK Kaibuchi
Nov 18, 2000·Experimental Cell Research·M AmanoK Kaibuchi
Oct 24, 2002·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Nina Wettschureck, Stefan Offermanns
Jun 5, 2003·Nature Reviews. Molecular Cell Biology·Kirsi Riento, Anne J Ridley
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

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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
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
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
Jan 11, 2014·The Journal of Biological Chemistry·Cendrine TouretteRobert E Hughes
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
Dec 2, 2020·Nanomedicine : Nanotechnology, Biology, and Medicine·Christian MacksJeoung Soo Lee
Jul 9, 2021·Frontiers in Cell and Developmental Biology·Faliang WangJieya Shao

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