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FEBS Lett. 2008 May 28;582(12):1637-42. doi: 10.1016/j.febslet.2008.04.009. Epub 2008 Apr 16.

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

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Department of Neurology, UCSF, GH-S572B, 600 16th Street, San Francisco, CA 94143, United States.


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.

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