Abstract
Myotonic dystrophy involves two types of chronically debilitating rare neuromuscular diseases: type 1 (DM1) and type 2 (DM2). Both share similarities in molecular cause, clinical signs, and symptoms with DM2 patients usually displaying milder phenotypes. It is well documented that key clinical symptoms in DM are associated with a strong mis-regulation of RNA metabolism observed in patient’s cells. This mis-regulation is triggered by two leading DM-linked events: the sequestration of Muscleblind-like proteins (MBNL) and the mis-regulation of the CUGBP RNA-Binding Protein Elav-Like Family Member 1 (CELF1) that cause significant alterations to their important functions in RNA processing. It has been suggested that DM1 may be treatable through endogenous modulation of the expression of MBNL and CELF1 proteins. In this study, we analyzed the recent identification of the involvement of microRNA (miRNA) molecules in DM and focus on the modulation of these miRNAs to therapeutically restore normal MBNL or CELF1 function. We also discuss additional prospective miRNA targets, the use of miRNAs as disease biomarkers, and additional promising miRNA-based and miRNA-targeting drug development strategies. This review provides a unifying overview of the dispersed data on miRNA available in the context of DM.
Highlights
Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are rare disorders caused by non-coding intragenic repeat tract expansions of CTG (DMPK gene) or CCTG (CNBP1 gene), which are pathogenic above 50 or 75 units, respectively [1]
A functional bond between some of these specific splicing events has been suggested with several key DM clinical phenotypes, such as chloride voltage-gated channel 1 (CLCN1) with myotonia [12], insulin receptor (INSR) with insulin resistance [13], sodium voltage-gated channel alpha subunit 5 (SCN5A), and troponin T2 cardiac type (TNNT2) with cardiac conduction defects [14], bridging integrator 1 (BIN1), voltage-gated channel subunit alpah1 S (CACNAS1), dystrophin (DMD), ryanodine receptor 1 (RYR1), and pyruvate kinase isozymes M1/M2 (PKM1/2) with muscle weakness and wasting [15,16,17], and microtubuleassociated protein tau (MAPT) with cognitive decline [18]
We describe why miRNAs are stimulating new therapeutic targets in DM with special attention paid to their connection with MBNLs and CUGBP Elav-Like Family Member 1 (CELF1) key disease factors
Summary
Myotonic dystrophy type 1 and type 2 (DM1 and DM2) are rare disorders caused by non-coding intragenic repeat tract expansions of CTG (DMPK gene) or CCTG (CNBP1 gene), which are pathogenic above 50 or 75 units, respectively [1]. The identification of tideglusib as an effective inhibitor of GSK3β for correcting CELF1 has shown the ability to improve functional aspects in different DM1 mouse models (HSALR and DMSXL) and patient-derived myoblasts [32] In this case, expectations are high for the results of the already completed phase II tideglusib DM1 clinical trial (NCT02858908). Discovered in the mid-1990s, miRNAs are a class of small non-coding RNAs (~22 nucleotides [nt] in length) with robust gene regulatory functions They promote mRNA messenger degradation, destabilization, or translation blocking (Figure 1A) with assistance from additional protein factors forming the RNA-induced silencing complex (RISC) [33]. We present a description of the current picture of miRNA dysregulation in DM
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