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

Lubov Timchenko

doi:10.3390/ijms21010094

Abstract

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.

Highlights

Complex Molecular Pathophysiology of DM1Myotonic dystrophy type 1 (DM1) is a complex genetic disease affecting many tissues, including skeletal and cardiac muscles, the brain, the eye and the endocrine system [1]
Dr Cooper’s group showed that the increase of CUGBP1 stability in DM1 is mediated by the increased phosphorylation of CUGBP1 by PKC kinase [32]. These findings suggest that PKC-mediated phosphorylation might control the affinity of CUGBP1 to the mutant DMPK mRNA, stabilizing CUGBP1 and increasing its levels
Other splicing targets of CUGBP1 include mRNAs, encoding F actin capping protein β subunit (Capzb), which contributes to filament growth [36]; muscle-specific chloride ion channel 1, that is needed for electrical stability of the membranes in skeletal muscle, contributing to myotonia in DM1 [59]; and insulin receptor, which plays a key role in the glucose homeostasis [60]

Summary

Introduction

Myotonic dystrophy type 1 (DM1) is a complex genetic disease affecting many tissues, including skeletal and cardiac muscles, the brain, the eye and the endocrine system [1]. Numerous molecular studies showed that DM1 is a “RNA disease”, which is caused by the accumulation of RNA CUG repeats that misregulate RNA metabolism in patients’ tissues via specific RNA-binding proteins (rev in [3,4]). In addition to CUGBP and MBNL families, the growing list of RNA-binding proteins, affected in DM1, includes RNA helicases DDX5 [5,6] and DDX6 [7], Staufen [8,9,10,11] and hnRNP H [12]. We will focus on the role of CUG repeats in the misregulation of the GSK3β-CUGBP1 pathway in DM1 pathogenesis and discuss recent findings, which describe how correction of this pathway may reduce DM1 and CDM1 pathology

Why Are Expanded RNA CUG Repeats Toxic?

The Role of Splicing Activity of CUGBP1 in DM1

CUGBP1 Is a Regulator of mRNA Stability

Inhibitors of GSK3 in DM1 and CDM1 Therapeutic Approaches

Conclusions