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Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 July 2020) | Viewed by 41331

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Prof. Dr. Lubov Timchenko

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Department of Pediatrics, Division of Neurology, Cincinnati Children’s Hospital, Medical Center, 3333 Burnet Ave, Cincinnati, OH, USA
Interests: genetic diseases with unstable expansions; RNA-binding proteins; molecular biology and biochemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Myotonic dystrophies (DM) type 1 and type 2 are complex genetic diseases affecting many tissues, including the skeletal muscle, heart and brain. DM1 and DM2 are caused by unstable expansions of CTG (DM1) and CCTG (DM2) repeats. Both diseases do not have a cure. The molecular studies of DM identified the major mechanisms for these disorders, associated with the toxic effects of the mutant RNAs, containing long CUG and CCUG repeats. However, the mutant RNAs in DM1 and DM2 might affect additional intracellular pathways, increasing the complexity of molecular pathogenesis. This Special Issue will summarize findings describing the molecular mechanisms of DM1 and DM2 and will discuss how these advances can be used for the development of the clinical studies in DM1 and DM2.

Prof. Lubov Timchenko
Guest Editor

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Published Papers (7 papers)

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Research

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23 pages, 2423 KiB

Open AccessArticle

Recovery in the Myogenic Program of Congenital Myotonic Dystrophy Myoblasts after Excision of the Expanded (CTG)n Repeat

by Laurène M. André, Remco T.P. van Cruchten, Marieke Willemse, Karel Bezstarosti, Jeroen A.A. Demmers, Ellen L. van Agtmaal, Derick G. Wansink and Bé Wieringa

Int. J. Mol. Sci. 2019, 20(22), 5685; https://doi.org/10.3390/ijms20225685 - 13 Nov 2019

Cited by 13 | Viewed by 3598

Abstract

The congenital form of myotonic dystrophy type 1 (cDM) is caused by the large-scale expansion of a (CTG•CAG)n repeat in DMPK and DM1-AS. The production of toxic transcripts with long trinucleotide tracts from these genes results in impairment of the myogenic differentiation capacity as cDM’s most prominent morpho-phenotypic hallmark. In the current in vitro study, we compared the early differentiation programs of isogenic cDM myoblasts with and without a (CTG)2600 repeat obtained by gene editing. We found that excision of the repeat restored the ability of cDM myoblasts to engage in myogenic fusion, preventing the ensuing myotubes from remaining immature. Although the cDM-typical epigenetic status of the DM1 locus and the expression of genes therein were not altered upon removal of the repeat, analyses at the transcriptome and proteome level revealed that early abnormalities in the temporal expression of differentiation regulators, myogenic progression markers, and alternative splicing patterns before and immediately after the onset of differentiation became normalized. Our observation that molecular and cellular features of cDM are reversible in vitro and can be corrected by repeat-directed genome editing in muscle progenitors, when already committed and poised for myogenic differentiation, is important information for the future development of gene therapy for different forms of myotonic dystrophy type 1 (DM1). Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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Review

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10 pages, 489 KiB

Open AccessReview

DM1 Phenotype Variability and Triplet Repeat Instability: Challenges in the Development of New Therapies

by Stéphanie Tomé and Geneviève Gourdon

Int. J. Mol. Sci. 2020, 21(2), 457; https://doi.org/10.3390/ijms21020457 - 10 Jan 2020

Cited by 24 | Viewed by 4524

Abstract

Myotonic dystrophy type 1 (DM1) is a complex neuromuscular disease caused by an unstable cytosine thymine guanine (CTG) repeat expansion in the DMPK gene. This disease is characterized by high clinical and genetic variability, leading to some difficulties in the diagnosis and prognosis of DM1. Better understanding the origin of this variability is important for developing new challenging therapies and, in particular, for progressing on the path of personalized treatments. Here, we reviewed CTG triplet repeat instability and its modifiers as an important source of phenotypic variability in patients with DM1. Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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18 pages, 1418 KiB

Open AccessReview

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

by Lubov Timchenko

Int. J. Mol. Sci. 2020, 21(1), 94; https://doi.org/10.3390/ijms21010094 - 21 Dec 2019

Cited by 12 | Viewed by 3809

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. Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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19 pages, 990 KiB

Open AccessReview

MicroRNA-Based Therapeutic Perspectives in Myotonic Dystrophy

by Arturo López Castel, Sarah Joann Overby and Rubén Artero

Int. J. Mol. Sci. 2019, 20(22), 5600; https://doi.org/10.3390/ijms20225600 - 9 Nov 2019

Cited by 26 | Viewed by 5002

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. Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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20 pages, 450 KiB

Open AccessReview

Mitigating RNA Toxicity in Myotonic Dystrophy using Small Molecules

by Kaalak Reddy, Jana R. Jenquin, John D. Cleary and J. Andrew Berglund

Int. J. Mol. Sci. 2019, 20(16), 4017; https://doi.org/10.3390/ijms20164017 - 17 Aug 2019

Cited by 15 | Viewed by 6621

Abstract

This review, one in a series on myotonic dystrophy (DM), is focused on the development and potential use of small molecules as therapeutics for DM. The complex mechanisms and pathogenesis of DM are covered in the associated reviews. Here, we examine the various small molecule approaches taken to target the DNA, RNA, and proteins that contribute to disease onset and progression in myotonic dystrophy type 1 (DM1) and 2 (DM2). Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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17 pages, 908 KiB

Open AccessReview

CRISPR/Cas Applications in Myotonic Dystrophy: Expanding Opportunities

by Renée H.L. Raaijmakers, Lise Ripken, C. Rosanne M. Ausems and Derick G. Wansink

Int. J. Mol. Sci. 2019, 20(15), 3689; https://doi.org/10.3390/ijms20153689 - 27 Jul 2019

Cited by 24 | Viewed by 6469

Abstract

CRISPR/Cas technology holds promise for the development of therapies to treat inherited diseases. Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder with a variable multisystemic character for which no cure is yet available. Here, we review CRISPR/Cas-mediated approaches that target the unstable (CTG•CAG)n repeat in the DMPK/DM1-AS gene pair, the autosomal dominant mutation that causes DM1. Expansion of the repeat results in a complex constellation of toxicity at the DNA level, an altered transcriptome and a disturbed proteome. To restore cellular homeostasis and ameliorate DM1 disease symptoms, CRISPR/Cas approaches were directed at the causative mutation in the DNA and the RNA. Specifically, the triplet repeat has been excised from the genome by several laboratories via dual CRISPR/Cas9 cleavage, while one group prevented transcription of the (CTG)n repeat through homology-directed insertion of a polyadenylation signal in DMPK. Independently, catalytically deficient Cas9 (dCas9) was recruited to the (CTG)n repeat to block progression of RNA polymerase II and a dCas9-RNase fusion was shown to degrade expanded (CUG)n RNA. We compare these promising developments in DM1 with those in other microsatellite instability diseases. Finally, we look at hurdles that must be taken to make CRISPR/Cas-mediated editing a therapeutic reality in patients. Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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20 pages, 3168 KiB

Open AccessReview

Short Tandem Repeat Expansions and RNA-Mediated Pathogenesis in Myotonic Dystrophy

by Łukasz J. Sznajder and Maurice S. Swanson

Int. J. Mol. Sci. 2019, 20(13), 3365; https://doi.org/10.3390/ijms20133365 - 9 Jul 2019

Cited by 53 | Viewed by 10302

Abstract

Short tandem repeat (STR) or microsatellite, expansions underlie more than 50 hereditary neurological, neuromuscular and other diseases, including myotonic dystrophy types 1 (DM1) and 2 (DM2). Current disease models for DM1 and DM2 propose a common pathomechanism, whereby the transcription of mutant DMPK (DM1) and CNBP (DM2) genes results in the synthesis of CUG and CCUG repeat expansion (CUG^exp, CCUG^exp) RNAs, respectively. These CUG^exp and CCUG^exp RNAs are toxic since they promote the assembly of ribonucleoprotein (RNP) complexes or RNA foci, leading to sequestration of Muscleblind-like (MBNL) proteins in the nucleus and global dysregulation of the processing, localization and stability of MBNL target RNAs. STR expansion RNAs also form phase-separated gel-like droplets both in vitro and in transiently transfected cells, implicating RNA-RNA multivalent interactions as drivers of RNA foci formation. Importantly, the nucleation and growth of these nuclear foci and transcript misprocessing are reversible processes and thus amenable to therapeutic intervention. In this review, we provide an overview of potential DM1 and DM2 pathomechanisms, followed by a discussion of MBNL functions in RNA processing and how multivalent interactions between expanded STR RNAs and RNA-binding proteins (RBPs) promote RNA foci assembly. Full article

(This article belongs to the Special Issue Myotonic Dystrophy: From Molecular Pathogenesis to Therapeutics)

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