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.