Brain Pathogenesis and Potential Therapeutic Strategies in Myotonic Dystrophy Type 1

Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy that affects multiple systems including the muscle and heart. The mutant CTG expansion at the 3′-UTR of the DMPK gene causes the expression of toxic RNA that aggregate as nuclear foci. The foci then interfere with RNA-binding proteins, affecting hundreds of mis-spliced effector genes, leading to aberrant alternative splicing and loss of effector gene product functions, ultimately resulting in systemic disorders. In recent years, increasing clinical, imaging, and pathological evidence have indicated that DM1, though to a lesser extent, could also be recognized as true brain diseases, with more and more researchers dedicating to develop novel therapeutic tools dealing with it. In this review, we summarize the current advances in the pathogenesis and pathology of central nervous system (CNS) deficits in DM1, intervention measures currently being investigated are also highlighted, aiming to promote novel and cutting-edge therapeutic investigations.

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Increased Muscleblind levels by chloroquine treatment improve myotonic dystrophy type 1 phenotypes in in vitro and in vivo models

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1820297116 ◽

2019 ◽

Vol 116 (50) ◽

pp. 25203-25213 ◽

Cited By ~ 4

Author(s):

Ariadna Bargiela ◽

Maria Sabater-Arcis ◽

Jorge Espinosa-Espinosa ◽

Miren Zulaica ◽

Adolfo Lopez de Munain ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Rna Binding ◽

Trinucleotide Repeat ◽

Rna Binding Proteins ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Muscle Area ◽

In Vivo Models

Myotonic dystrophy type 1 (DM1) is a life-threatening and chronically debilitating neuromuscular disease caused by the expansion of a CTG trinucleotide repeat in the 3′ UTR of the DMPK gene. The mutant RNA forms insoluble structures capable of sequestering RNA binding proteins of the Muscleblind-like (MBNL) family, which ultimately leads to phenotypes. In this work, we demonstrate that treatment with the antiautophagic drug chloroquine was sufficient to up-regulate MBNL1 and 2 proteins in Drosophila and mouse (HSALR) models and patient-derived myoblasts. Extra Muscleblind was functional at the molecular level and improved splicing events regulated by MBNLs in all disease models. In vivo, chloroquine restored locomotion, rescued average cross-sectional muscle area, and extended median survival in DM1 flies. In HSALR mice, the drug restored muscular strength and histopathology signs and reduced the grade of myotonia. Taken together, these results offer a means to replenish critically low MBNL levels in DM1.

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High-throughput kinome-RNAi screen identifies protein kinase R activator (PACT) as a novel genetic modifier of CUG foci integrity in myotonic dystrophy type 1 (DM1)

PLoS ONE ◽

10.1371/journal.pone.0256276 ◽

2021 ◽

Vol 16 (9) ◽

pp. e0256276

Author(s):

Nafisa Neault ◽

Sean O’Reilly ◽

Aiman Tariq Baig ◽

Julio Plaza-Diaz ◽

Mehrdad Azimi ◽

...

Keyword(s):

Protein Kinase ◽

Myotonic Dystrophy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Genetic Modifier ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Aberrant Expression ◽

Significant Correction

Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy (~1:8000). In DM1, expansion of CTG trinucleotide repeats in the 3’ untranslated region of the dystrophia myotonica protein kinase (DMPK) gene results in DMPK mRNA hairpin structures which aggregate as insoluble ribonuclear foci and sequester several RNA-binding proteins. The resulting sequestration and misregulation of important splicing factors, such as muscleblind-like 1 (MBNL1), causes the aberrant expression of fetal transcripts for several genes that contribute to the disease phenotype. Previous work has shown that antisense oligonucleotide-mediated disaggregation of the intranuclear foci has the potential to reverse downstream anomalies. To explore whether the nuclear foci are, to some extent, controlled by cell signalling pathways, we have performed a screen using a small interfering RNA (siRNA) library targeting 518 protein kinases to look at kinomic modulation of foci integrity. RNA foci were visualized by in situ hybridization of a fluorescent-tagged (CAG)10 probe directed towards the expanded DMPK mRNA and the cross-sectional area and number of foci per nuclei were recorded. From our screen, we have identified PACT (protein kinase R (PKR) activator) as a novel modulator of foci integrity and have shown that PACT knockdown can both increase MBNL1 protein levels; however, these changes are not suffcient for significant correction of downstream spliceopathies.

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A comprehensive atlas of fetal splicing patterns in the brain of adult myotonic dystrophy type 1 patients

10.1101/2021.10.01.462715 ◽

2021 ◽

Author(s):

Max J. F. Degener ◽

Remco T.P. van Cruchten ◽

Brittney A. Otero ◽

Eric T. Wang ◽

Derick G. Wansink ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Rna Binding ◽

Rna Binding Proteins ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Healthy Individuals ◽

Developmentally Regulated ◽

The Central Nervous System ◽

Splicing Patterns

ABSTRACTIn patients with myotonic dystrophy type 1 (DM1), dysregulation of RNA-binding proteins like MBNL and CELF1 leads to alternative splicing of exons and is thought to induce a return to fetal splicing patterns in adult tissues, including the central nervous system (CNS). To comprehensively evaluate this, we created an atlas of developmentally regulated splicing patterns in the frontal cortex of healthy individuals and DM1 patients by combining RNA-seq data from BrainSpan, GTEx and DM1 patients. Thirty four splice events displayed an inclusion pattern in DM1 patients that is typical for the fetal situation in healthy individuals. The regulation of DM1-relevant splicing patterns could partly be explained by changes in mRNA expression of the splice regulators MBNL1, MBNL2 and CELF1. On the contrary, interindividual differences in splicing patterns between healthy adults could not be explained by differential expression of these splice regulators. Our findings lend transcriptome-wide evidence to the previously noted shift to fetal splicing patterns in the adult DM1 brain as a consequence of an imbalance in antagonistic MBNL and CELF1 activities. Our atlas serves as a solid foundation for further study and understanding of the cognitive phenotype in patients.

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

International Journal of Molecular Sciences ◽

10.3390/ijms21010094 ◽

2019 ◽

Vol 21 (1) ◽

pp. 94 ◽

Cited By ~ 2

Author(s):

Lubov Timchenko

Keyword(s):

Myotonic Dystrophy ◽

Complex Disease ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Ctg Repeats ◽

Toxic Rna

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.

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Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients

Journal of Neuromuscular Diseases ◽

10.3233/jnd-200558 ◽

2021 ◽

pp. 1-17

Author(s):

Valentina Grande ◽

Denisa Hathazi ◽

Emily O′Connor ◽

Theo Marteau ◽

Ulrike Schara-Schmidt ◽

...

Keyword(s):

Skeletal Muscle ◽

Myotonic Dystrophy ◽

Rna Binding ◽

Glycogen Synthase ◽

Muscle Cells ◽

Skeletal Muscle Cells ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Treatment Responses

Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3′-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3β), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3β-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3βby unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80– 150) and high (2600– 3600) CTG-repeats. Apart from GSK3β increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3β. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3β inhibitor treatment responses.

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Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in Myotonic Dystrophy type 1

10.1101/431569 ◽

2018 ◽

Author(s):

Emilie Plantié ◽

Masayuki Nakamori ◽

Yoan Renaud ◽

Aline Huguet ◽

Caroline Choquet ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Rna Binding ◽

Cardiac Cells ◽

Cardiac Conduction ◽

Regulatory Subunit ◽

Conduction Delay ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Intraventricular Conduction

ABSTRACTCardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a complex toxic CTG repeat disorder involving misbalance between two RNA- binding factors, MBNL1 and CELF1. How this pathogenic DM1 condition translates into cardiac conduction disorders remains poorly understood. Here, we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and identified associated gene deregulations using TU-tagging based transcriptional profiling of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels and among them increased expression of straightjacket/α2δ3 that encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heart beating, a hallmark of affected conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular α2δ3 expression is low in healthy mice and humans but significantly elevated in ventricular muscles from DM1 patients with conduction defects. Taken together, this suggests that reducing the straightjacket/α2δ3 transcript levels in ventricular cardiomyocytes could represent a strategy to prevent conduction defects and in particular intraventricular conduction delay associated with DM1 pathology.

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Straightjacket/α2δ3 deregulation is associated with cardiac conduction defects in myotonic dystrophy type 1

eLife ◽

10.7554/elife.51114 ◽

2019 ◽

Vol 8 ◽

Author(s):

Emilie Auxerre-Plantié ◽

Masayuki Nakamori ◽

Yoan Renaud ◽

Aline Huguet ◽

Caroline Choquet ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Rna Binding ◽

Cardiac Cells ◽

Cardiac Conduction ◽

Regulatory Subunit ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Conduction Disorders ◽

Decrease Life Expectancy

Cardiac conduction defects decrease life expectancy in myotonic dystrophy type 1 (DM1), a CTG repeat disorder involving misbalance between two RNA binding factors, MBNL1 and CELF1. However, how DM1 condition translates into conduction disorders remains poorly understood. Here we simulated MBNL1 and CELF1 misbalance in the Drosophila heart and performed TU-tagging-based RNAseq of cardiac cells. We detected deregulations of several genes controlling cellular calcium levels, including increased expression of straightjacket/α2δ3, which encodes a regulatory subunit of a voltage-gated calcium channel. Straightjacket overexpression in the fly heart leads to asynchronous heartbeat, a hallmark of abnormal conduction, whereas cardiac straightjacket knockdown improves these symptoms in DM1 fly models. We also show that ventricular α2δ3 expression is low in healthy mice and humans, but significantly elevated in ventricular muscles from DM1 patients with conduction defects. These findings suggest that reducing ventricular straightjacket/α2δ3 levels could offer a strategy to prevent conduction defects in DM1.

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