ROCK and PRK-2 mediate the inhibitory effect of Y-27632 on polyglutamine aggregation.
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.
Shao
Jieya
J
Department of Neurology, UCSF, GH-S572B, 600 16th Street, San Francisco, CA 94143, United States.
Welch
William J
WJ
Diamond
Marc I
MI
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy; D009125:Muscle Relaxants, Central / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D034622:RNA Interference; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D000577:Amides; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009125:Muscle Relaxants, Central; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; C097188:polyglutamine; C061570:protein kinase N; D054460:rho-Associated Kinases; D011493:Protein Kinase C