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High-content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC-independent pathway in myotonic dystrophy cell lines

Ketley, Ami; Chen, Catherine Z.; Li, Xin; Arya, Sukrat; Robinson, Thelma E.; Granados-Riveron, Javier T.; Udosen, Inyang; Morris, Glenn E.; Holt, Ian; Furling, Dennis; Chaouch, Soraya; Haworth, Ben; Southall, Noel; Shinn, Paul; Zheng, Wei; Austin, Christopher P.; Hayes, Christopher J.; Brook, J. David

Authors

Ami Ketley

Catherine Z. Chen

Xin Li

Sukrat Arya

Thelma E. Robinson

Javier T. Granados-Riveron

Inyang Udosen

Glenn E. Morris

Ian Holt

Dennis Furling

Soraya Chaouch

Ben Haworth

Noel Southall

Paul Shinn

Wei Zheng

Christopher P. Austin

CHRIS HAYES chris.hayes@nottingham.ac.uk
Professor of Organic Chemistry

DAVID BROOK david.brook@nottingham.ac.uk
Professor of Human Genetics



Abstract

Myotonic dystrophy (DM) is a multi-system neuromuscular disorder for which there is no treatment. We have developed a medium throughput phenotypic assay, based on the identification of nuclear foci in DM patient cell lines using in situ hybridization and high-content imaging to screen for potentially useful therapeutic compounds. A series of further assays based on molecular features of DM have also been employed. Two compounds that reduce and/or remove nuclear foci have been identified, Ro 31-8220 and chromomycin A3. Ro 31-8220 is a PKC inhibitor, previously shown to affect the hyperphosphorylation of CELF1 and ameliorate the cardiac phenotype in a DM1 mouse model. We show that the same compound eliminates nuclear foci, reduces MBNL1 protein in the nucleus, affects ATP2A1 alternative splicing and reduces steady-state levels of CELF1 protein. We demonstrate that this effect is independent of PKC activity and conclude that this compound may be acting on alternative kinase targets within DM pathophysiology. Understanding the activity profile for this compound is key for the development of targeted therapeutics in the treatment of DM.

Citation

Ketley, A., Chen, C. Z., Li, X., Arya, S., Robinson, T. E., Granados-Riveron, J. T., …Brook, J. D. (2014). High-content screening identifies small molecules that remove nuclear foci, affect MBNL distribution and CELF1 protein levels via a PKC-independent pathway in myotonic dystrophy cell lines. Human Molecular Genetics, 23(6), doi:10.1093/hmg/ddt542

Journal Article Type Article
Publication Date Mar 6, 2014
Deposit Date Apr 15, 2014
Publicly Available Date Apr 15, 2014
Journal Human Molecular Genetics
Print ISSN 0964-6906
Electronic ISSN 1460-2083
Publisher Oxford University Press (OUP)
Peer Reviewed Peer Reviewed
Volume 23
Issue 6
DOI https://doi.org/10.1093/hmg/ddt542
Public URL http://eprints.nottingham.ac.uk/id/eprint/2905
Publisher URL http://hmg.oxfordjournals.org/content/23/6/1551
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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