Phosphorylation of profilin by ROCK1 regulates polyglutamine aggregation
Open accessAbstract
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.
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From an in vitro screen for molecules that reduce polyglutamine toxicity, the ROCK-inhibitor Y27632 was identified and subsequently shown to reduce Htt aggregation in cultured cells and Htt-mediated neurodegeneration in drosophila.
“From an in vitro screen for molecules that reduce polyglutamine toxicity, the ROCK-inhibitor Y27632 was identified and subsequently shown to reduce Htt aggregation in cultured cells and Htt-mediated neurodegeneration in drosophila [197,198].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [198]
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MACDONALD, M. (1993) · Cell · doi:10.1016/0092-8674(93)90585-e · Cited by 8,366 · see citing works
Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease
Ferrante, R. J., Andreassen, O. A., Jenkins, B. G., Dedeoglu, A., Kuemmerle, S., Kubilus, J. K., Kaddurah-Daouk, R., Hersch, S. M., & Beal, M. F. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-12-04389.2000 · Cited by 522 · see citing works
Ferrante, R. J., Andreassen, O. A., Dedeoglu, A., Ferrante, K. L., Jenkins, B. G., Hersch, S. M., & Beal, M. F. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01592.2002 · Cited by 391 · see citing works
Andreassen, O. A., Dedeoglu, A., Ferrante, R. J., Jenkins, B. G., Ferrante, K. L., Thomas, M., Friedlich, A., Browne, S. E., Schilling, G., Borchelt, D. R., et al. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2001.0406 · Cited by 293 · see citing works
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Research works printed but not linked: 5
- [11]11. Diamond, M. I., M. R. Robinson, and K. R. Yamamoto. 2000. Regulation of expanded polyglutamine protein aggregation and nuclear localization by the glucocorticoid receptor. Proc. Natl. Acad. Sci. USA 97: 657-661.
- [18]18. Hockly, E., V. M. Richon, B. Woodman, D. L. Smith, X. Zhou, E. Rosa, K. Sathasivam, S. Ghazi-Noori, A. Mahal, P. A. Lowden, J. S. Steffan, J. L. Marsh, L. M. Thompson, C. M. Lewis, P. A. Marks, and G. P. Bates. 2003. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl. Acad. Sci. USA 100: 2041-2046.
- [21]21. Karpuj, M. V., M. W. Becher, J. E. Springer, D. Chabas, S. Youssef, R. Pedotti, D. Mitchell, and L. Steinman. 2002. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nat. Med. 8: 143-149.
- [31]31. Muchowski, P. J., G. Schaffar, A. Sittler, E. E. Wanker, M. K. Hayer-Hartl, and F. U. Hartl. 2000. hsp70 and hsp40 chaperones can inhibit self-assembly of polyglutamine proteins into amyloid-like fibrils. Proc. Natl. Acad. Sci. USA 97: 7841-7846.
- [49]49. Wang, X., S. Zhu, M. Drozda, W. Zhang, I. G. Stavrovskaya, E. Cattaneo, R. J. Ferrante, B. S. Kristal, and R. M. Friedlander. 2003. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc. Natl. Acad. Sci. USA 100: 10483-10487.
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RhoA Signaling in Neurodegenerative Diseases
Schmidt, S. I., Blaabjerg, M., Freude, K., & Meyer, M. (2022) · Cells · doi:10.3390/cells11091520 · Cited by 110 · see citing works
Rho GTPases in neurodegeneration diseases
DeGeer, J., & Lamarche-Vane, N. (2013) · Experimental Cell Research · doi:10.1016/j.yexcr.2013.06.016 · Cited by 46 · see citing works
- Authors
- Shao, J., Welch, W. J., DiProspero, N. A., & Diamond, M. I.
- Affiliations
- University of California, San Francisco (US)
- National Institutes of Health (US)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2008-09-01
- Volume
- 28
- Issue
- 17
- Pages
- 5196-5208
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2519718
- OpenAlex
- W2112516420
- Cited by
- 171
- References
- 4
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 8 · 2023: 2 · 2022: 8 · 2021: 23 · 2020: 14 · 2019: 7 · 2018: 9 · 2017: 8 · 2016: 8 · 2015: 8 · 2014: 14 · 2013: 11 · 2012: 13
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- profilin, ROCK1, phosphorylation, polyglutamine aggregation, Huntington's disease, huntingtin, androgen receptor, Y-27632, Rho kinase, G-actin binding, protein aggregation, therapeutic target
- MeSH terms
- Actins, Amides, Animals, Cell Line, Chickens, Humans, Models, Biological, Nerve Tissue Proteins, Neurons, Peptides, Phosphorylation, Phosphoserine, Protein Binding, Pyridines, Receptors, Androgen, Signal Transduction, rho GTP-Binding Proteins, Protein Structure, Quaternary, Profilins, Rats, rho-Associated Kinases
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