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

Jieya Shao, William J. Welch, Marc I. Diamond

Research output: Contribution to journalArticle

22 Scopus citations

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 languageEnglish (US)
Pages (from-to)1637-1642
Number of pages6
JournalFEBS Letters
Volume582
Issue number12
DOIs
StatePublished - May 28 2008

Keywords

  • Androgen receptor
  • Huntingtin
  • Neurodegeneration
  • PRK-2
  • Polyglutamine
  • ROCK

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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