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Mol Cell Biol. 2008 Sep;28(17):5196-208. doi: 10.1128/MCB.00079-08. Epub 2008 Jun 23.

Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation.

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  • 1Departments of Neurology and Cellular and Molecular Pharmacology, UCSF, San Francisco, California 94143, USA.

Abstract

Y-27632, an inhibitor of the Rho-associated kinase ROCK, is a therapeutic lead for Huntington disease (HD). The downstream targets that mediate its inhibitory effects on huntingtin (Htt) aggregation and toxicity are unknown. We have identified profilin, a small actin-binding factor that also interacts with Htt, as being a direct target of the ROCK1 isoform. The overexpression of profilin reduces the aggregation of polyglutamine-expanded Htt and androgen receptor (AR) peptides. This requires profilin's G-actin binding activity and its direct interaction with Htt, which are both inhibited by the ROCK1-mediated phosphorylation of profilin at Ser-137. Y-27632 blocks the phosphorylation of profilin in HEK293 cells and primary neurons, which maintains profilin in an active state. The knockdown of profilin blocks the inhibitory effect of Y-27632 on both AR and Htt aggregation. A signaling pathway from ROCK1 to profilin thus controls polyglutamine protein aggregation and is targeted by a promising therapeutic lead for HD.

PMID:
18573880
[PubMed - indexed for MEDLINE]
PMCID:
PMC2519718
Free PMC Article

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