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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / pharmacology*
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Animals
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Cell Line
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Drosophila
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Humans
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Huntingtin Protein
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Huntington Disease / drug therapy
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Muscle Relaxants, Central / pharmacology*
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptides / antagonists & inhibitors*
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Peptides / metabolism
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Protein Kinase C / antagonists & inhibitors*
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Protein Kinase C / genetics
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Protein Kinase C / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Pyridines / pharmacology*
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RNA Interference
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rho-Associated Kinases / antagonists & inhibitors*
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism
Substances
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Amides
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HTT protein, human
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Huntingtin Protein
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Muscle Relaxants, Central
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Protein Kinase Inhibitors
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Pyridines
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Y 27632
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polyglutamine
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protein kinase N
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rho-Associated Kinases
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Protein Kinase C