FEBS Letters
Volume 582, Issue 12 , Pages 1637-1642, 28 May 2008

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

Edited by Barry Halliwell

  • Jieya Shao

      Affiliations

    • Department of Neurology, UCSF, GH-S572B, 600 16th Street, San Francisco, CA 94143, United States
    • Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA 94143, United States
    • ,
  • William J. Welch

      Affiliations

    • Department of Surgery, UCSF, San Francisco, CA 94143, United States
    • ,
  • Marc I. Diamond

      Affiliations

    • Department of Neurology, UCSF, GH-S572B, 600 16th Street, San Francisco, CA 94143, United States
    • Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, CA 94143, United States
    • Corresponding Author InformationCorresponding author. Address: Department of Neurology, UCSF, GH-S572B, 600 16th Street, San Francisco, CA 94143-2280, United States. Fax: +1 415 514 4112.

Received 4 April 2008; accepted 9 April 2008. published online 16 April 2008.

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.

Keywords: Polyglutamine, Neurodegeneration, ROCK, PRK-2, Huntingtin, Androgen receptor

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PII: S0014-5793(08)00323-2

doi:10.1016/j.febslet.2008.04.009

FEBS Letters
Volume 582, Issue 12 , Pages 1637-1642, 28 May 2008

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