Small Molecules Which Improve Pathogenesis of Myotonic Dystrophy Type 1

Abstract

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults for which there is currently no treatment. The pathogenesis of this autosomal dominant disorder is associated with the expansion of CTG repeats in the 3'-UTR of the DMPK gene. DMPK transcripts with expanded CUG repeats (CUG^expDMPK) are retained in the nucleus forming multiple discrete foci, and their presence triggers a cascade of toxic events. Thus far, most research emphasis has been on interactions of CUG^expDMPK with the muscleblind-like (MBNL) family of splicing factors. These proteins are sequestered by the expanded CUG repeats of DMPK RNA leading to their functional depletion. As a consequence, abnormalities in many pathways of RNA metabolism, including alternative splicing, are detected in DM1. To date, in vitro and in vivo efforts to develop therapeutic strategies for DM1 have mostly been focused on targeting CUG^expDMPK via reducing their expression and/or preventing interactions with MBNL1. Antisense oligonucleotides targeted to the CUG repeats in the DMPK transcripts are of particular interest due to their potential capacity to discriminate between mutant and normal transcripts. However, a growing number of reports describe alternative strategies using small molecule chemicals acting independently of a direct interaction with CUG^expDMPK. In this review, we summarize current knowledge about these chemicals and we describe the beneficial effects they caused in different DM1 experimental models. We also present potential mechanisms of action of these compounds and pathways they affect which could be considered for future therapeutic interventions in DM1.

Keywords: aberrant alternative splicing; antisense oligonucleotides; myotonic dystrophy type 1; myotonic dystrophy type 1 pathogenesis; sequestration of muscleblind-like 1; small molecule compounds.

Figure 1

Small molecule compounds alleviating myotonic dystrophy type 1 (DM1) pathogenesis. Small molecule compounds which mitigated DM1 pathogenesis in different experimental systems are shown. The molecules are classified into a few categories depending on their presumable mechanisms of action. All the molecules are believed to act independently of direct interactions with expanded CUG repeats RNA.

Figure 2

Therapeutic effects of small molecules on myotonic dystrophy type 1 (DM1) pathogenesis. DM1 is characterized by the presence of RNA foci which are aggregations of the mutant CUG^exp transcript with muscleblind-like (MBNL)1 and other proteins. CUGBP1 is not sequestered by foci, but it is upregulated. The imbalance of these two alternative splicing proteins causes the aberrant alternative splicing of many pre-mRNAs. Treatment of DM1 cells and model organisms with small molecules that target the DNA and/or affect proteins involved in the DM1 pathogenesis can lead to beneficial effects, such as inhibition of transcription of the mutant transcript, or its degradation, release of MBNL1 protein from RNA foci, downregulation of CUGBP1 protein, and ultimately the correction of the aberrant splicing.