Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation

Jieya Shao, William J. Welch, Nicholas A. DiProspero, Marc I. Diamond

Research output: Contribution to journalArticle

85 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5196-5208
Number of pages13
JournalMolecular and Cellular Biology
Volume28
Issue number17
DOIs
StatePublished - Sep 2008

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Profilins
Phosphorylation
Huntington Disease
Androgen Receptors
Actins
Receptor Aggregation
rho-Associated Kinases
polyglutamine
HEK293 Cells
Protein Isoforms
Neurons
Peptides

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. / Shao, Jieya; Welch, William J.; DiProspero, Nicholas A.; Diamond, Marc I.

In: Molecular and Cellular Biology, Vol. 28, No. 17, 09.2008, p. 5196-5208.

Research output: Contribution to journalArticle

Shao, Jieya ; Welch, William J. ; DiProspero, Nicholas A. ; Diamond, Marc I. / Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation. In: Molecular and Cellular Biology. 2008 ; Vol. 28, No. 17. pp. 5196-5208.
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