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.
Original language | English |
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Pages (from-to) | 1637-1642 |
Number of pages | 6 |
Journal | FEBS Letters |
Volume | 582 |
Issue number | 12 |
DOIs | |
State | Published - May 28 2008 |
Keywords
- Androgen receptor
- Huntingtin
- Neurodegeneration
- PRK-2
- Polyglutamine
- ROCK