Developmental insights into the pathology of and therapeutic strategies for DM1: Back to the basics

Abstract

Myotonic Dystrophy type 1 (DM1), the most prevalent adult onset muscular dystrophy, is a trinucleotide repeat expansion disease caused by CTG expansion in the 3 0 -UTR of DMPK gene. This expansion results in the expression of toxic gain-of-function RNA that forms ribonuclear foci and disrupts normal activities of RNA-binding proteins belonging to the MBNL and CELF families. Changes in alternative splicing, translation, localization, and mRNA stability due to sequestration of MBNL proteins and up-regulation of CELF1 are key to DM1 pathology. However, recent discoveries indicate that pathogenic mechanisms of DM1 involves many other factors as well, including repeat associated translation, activation of PKC-dependent signaling pathway, aberrant polyadenylation, and microRNA deregulation. Expression of the toxic repeat RNA culminates in the developmental remodeling of the transcriptome, which produces fetal isoforms of proteins that are unable to fulfill the physiological requirements of adult tissues. This review will describe advances in the understanding of DM1 pathogenesis as well as current therapeutic developments for DM1. Developmental Dynamics 244:377-390, 2015. V C 2014 Wiley Periodicals, Inc.

Mechanistic determinants of MBNL activity

“…Generally, MBNL paralogs bind to CUG repeats and dissociate from them when MBNL is in a saturated state (Figure 7B, left panel). In DM1 and DM2, the sequestration of proteins on C(C)UG exp leads to a significant reduction in the free MBNL pool available for normal RNA splicing targets and this situation impacts global AS and APA regulation (57). Effective sequestration of MBNL activity depends on the length of the repeat tract which is modulated by somatic expansion during the lifespan of DM1 patients.…”

RNA toxicity and foci formation in microsatellite expansion diseases

“…Changes of MBNL1 and CUGBP1/CELF1 in DM1 drive splicing of a variety of transcripts towards fetal isoforms. Many of the misspliced genes are components of the sodium/calcium current regulation, intra-/inter-cellular transport, and sarcomere/cytoskeleton structure and function [89,90]. They are thus unable to fulfill their normal cellular functions.…”

LOX-1 and Its Splice Variants: A New Challenge for Atherosclerosis and Cancer-Targeted Therapies

“…MBNL1 and CELF1 are both essential for a normal splicing regulation of many pre-mRNAs during development [59,60]. In this scenario, the disruption of their functions by CUG exp RNA leads to missplicing of a number of genes such as the muscle-specific chloride channel ( CLCN1 ) gene, bridging integrator 1 ( BIN1 ) gene, insulin receptor ( IR ) gene, pyruvate kinase M ( PKM ) gene, and cardiac troponin T ( TNNT2 ) gene, all of which represent the prominent characteristics of the disease [61]. The alteration of IR and CLCN1 pre-mRNA processing points toward the hypothesis of a spliceopathy, which leads to an inadequate expression of isoforms for a particular tissue or developmental stage [62].…”