Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

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Dissecting Pathogenetic Mechanisms and Therapeutic Strategies in Drosophila Models of Myotonic Dystrophy Type 1

International Journal of Molecular Sciences ◽

10.3390/ijms19124104 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4104 ◽

Cited By ~ 3

Author(s):

Anissa Souidi ◽

Monika Zmojdzian ◽

Krzysztof Jagla

Keyword(s):

Myotonic Dystrophy ◽

Heart Defects ◽

Fruit Fly ◽

Therapeutic Strategies ◽

Testicular Atrophy ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Genetic Modifiers ◽

Multisystemic Disease

Myotonic dystrophy type 1 (DM1), the most common cause of adult-onset muscular dystrophy, is autosomal dominant, multisystemic disease with characteristic symptoms including myotonia, heart defects, cataracts and testicular atrophy. DM1 disease is being successfully modelled in Drosophila allowing to identify and validate new pathogenic mechanisms and potential therapeutic strategies. Here we provide an overview of insights gained from fruit fly DM1 models, either: (i) fundamental with particular focus on newly identified gene deregulations and their link with DM1 symptoms; or (ii) applied via genetic modifiers and drug screens to identify promising therapeutic targets.

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Differences in splicing defects between the grey and white matter in myotonic dystrophy type 1

10.1101/819433 ◽

2019 ◽

Author(s):

Masamitsu Nishi ◽

Takashi Kimura ◽

Mitsuru Furuta ◽

Koichi Suenaga ◽

Tsuyoshi Matsumura ◽

...

Keyword(s):

White Matter ◽

Myotonic Dystrophy ◽

Cell Body ◽

Neuronal Cell ◽

Neuronal Cell Body ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

And Control ◽

The Brain

AbstractMyotonic dystrophy type 1 (DM1) is a multi-system disorder caused by CTG repeats in the myotonic dystrophy protein kinase (DMPK) gene. This leads to sequestration of the splicing factor, muscleblind-like 2 (MBNL2), and aberrant splicing, mainly in the central nervous system. We investigated the splicing patterns of MBNL1/2 and genes controlled by MBNL2 in several regions of the brain and between the grey matter (GM) and white matter (WM) in DM1 patients using RT-PCR. Compared with the control, the percentage of spliced-in parameter (PSI) for most of the examined exons were significantly altered in most of the brain regions of DM1 patients, except for the cerebellum. The splicing of many genes was differently regulated between the GM and WM in both DM1 and control. The level of change in PSI between DM1 and control was higher in the GM than in the WM. The differences in alternative splicing between the GM and WM may be related to the effect of DM1 on the WM of the brain. We hypothesize that in DM1, aberrantly spliced isoforms in the neuronal cell body of the GM may not be transported to the axon. This might affect the WM as a consequence of Wallerian degeneration secondary to cell body damage. Our findings may have implications for analysis of the pathological mechanisms and exploring potential therapeutic targets.

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Myotonic Dystrophy Type 1 (DM1): From the Genetics to Molecular Mechanisms

Muscular Dystrophy ◽

10.5772/30209 ◽

2012 ◽

Author(s):

Jonathan J. ◽

Bulmaro Cisneros

Keyword(s):

Myotonic Dystrophy ◽

Molecular Mechanisms ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type

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MRI findings and cognitive functions in a small cohort of myotonic dystrophy type 1: Retrospective analyses

The Neuroradiology Journal ◽

10.1177/1971400916678223 ◽

2016 ◽

Vol 30 (1) ◽

pp. 23-27 ◽

Cited By ~ 6

Author(s):

Arsida Bajrami ◽

Filiz Azman ◽

Vildan Yayla ◽

Sultan Cagirici ◽

Cahit Keskinkiliç ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Cognitive Deficits ◽

Morphological Changes ◽

Brain Mri ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Mri Findings ◽

Multisystemic Disease ◽

Systemic Symptoms

Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease with common cognitive deficits and potential brain involvement in addition to the cardinal muscular and systemic symptoms. Impaired mental function associated with nonspecific pathological findings such as white-matter hyperintense lesions (WMHLs), ventricular enlargement and brain atrophy on brain MRI have been previously reported in DM1 patients. While some studies showed correlation of brain morphological changes with neuropsychological and clinical parameters including CTG repeat sizes and disease severity scales in DM1, others failed. The goal of this study was to retrospectively investigate cranial MR abnormalities, predominantly WMHLs, and their effects on clinical and cognitive deficits in a small, phenotypically or genotypically well-characterized cohort of DM1 patients.

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Metabolic Alterations in Myotonic Dystrophy Type 1 and Their Correlation with Lipin

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18041794 ◽

2021 ◽

Vol 18 (4) ◽

pp. 1794

Author(s):

Tiago Mateus ◽

Filipa Martins ◽

Alexandra Nunes ◽

Maria Teresa Herdeiro ◽

Sandra Rebelo

Keyword(s):

Metabolic Syndrome ◽

Myotonic Dystrophy ◽

Molecular Mechanisms ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Inflammasome Activation ◽

Myotonic Dystrophy Type 1 ◽

Myotonic Dystrophy Type ◽

Metabolic Alterations

Myotonic dystrophy type 1 (DM1) is an autosomal dominant hereditary and multisystemic disease, characterized by progressive distal muscle weakness and myotonia. Despite huge efforts, the pathophysiological mechanisms underlying DM1 remain elusive. In this review, the metabolic alterations observed in patients with DM1 and their connection with lipin proteins are discussed. We start by briefly describing the epidemiology, the physiopathological and systemic features of DM1. The molecular mechanisms proposed for DM1 are explored and summarized. An overview of metabolic syndrome, dyslipidemia, and the summary of metabolic alterations observed in patients with DM1 are presented. Patients with DM1 present clinical evidence of metabolic alterations, namely increased levels of triacylglycerol and low-density lipoprotein, increased insulin and glucose levels, increased abdominal obesity, and low levels of high-density lipoprotein. These metabolic alterations may be associated with lipins, which are phosphatidate phosphatase enzymes that regulates the triacylglycerol levels, phospholipids, lipid signaling pathways, and are transcriptional co-activators. Furthermore, lipins are also important for autophagy, inflammasome activation and lipoproteins synthesis. We demonstrate the association of lipin with the metabolic alterations in patients with DM1, which supports further clinical studies and a proper exploration of lipin proteins as therapeutic targets for metabolic syndrome, which is important for controlling many diseases including DM1.

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