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Correction of RNA-Binding Protein CUGBP1 and GSK3β Signaling as Therapeutic Approach for Congenital and Adult Myotonic Dystrophy Type 1

Departments of Neurology and Pediatrics, Cincinnati Children’s Hospital Medical Center and the University of Cincinnati, Cincinnati, OH 45229, USA
Int. J. Mol. Sci. 2020, 21(1), 94; https://doi.org/10.3390/ijms21010094
Received: 26 November 2019 / Revised: 13 December 2019 / Accepted: 17 December 2019 / Published: 21 December 2019
(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)
Myotonic dystrophy type 1 (DM1) is a complex genetic disease affecting many tissues. DM1 is caused by an expansion of CTG repeats in the 3′-UTR of the DMPK gene. The mechanistic studies of DM1 suggested that DMPK mRNA, containing expanded CUG repeats, is a major therapeutic target in DM1. Therefore, the removal of the toxic RNA became a primary focus of the therapeutic development in DM1 during the last decade. However, a cure for this devastating disease has not been found. Whereas the degradation of toxic RNA remains a preferential approach for the reduction of DM1 pathology, other approaches targeting early toxic events downstream of the mutant RNA could be also considered. In this review, we discuss the beneficial role of the restoring of the RNA-binding protein, CUGBP1/CELF1, in the correction of DM1 pathology. It has been recently found that the normalization of CUGBP1 activity with the inhibitors of GSK3 has a positive effect on the reduction of skeletal muscle and CNS pathologies in DM1 mouse models. Surprisingly, the inhibitor of GSK3, tideglusib also reduced the toxic CUG-containing RNA. Thus, the development of the therapeutics, based on the correction of the GSK3β-CUGBP1 pathway, is a promising option for this complex disease. View Full-Text
Keywords: myotonic dystrophy; congenital myotonic dystrophy; CUGBP1; GSK3β signaling; GSK3 inhibitors myotonic dystrophy; congenital myotonic dystrophy; CUGBP1; GSK3β signaling; GSK3 inhibitors
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Timchenko, L. Correction of RNA-Binding Protein CUGBP1 and GSK3β Signaling as Therapeutic Approach for Congenital and Adult Myotonic Dystrophy Type 1. Int. J. Mol. Sci. 2020, 21, 94.

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