scholarly journals Cellular and molecular mechanisms underlying muscular dystrophy

2013 ◽  
Vol 201 (4) ◽  
pp. 499-510 ◽  
Author(s):  
Fedik Rahimov ◽  
Louis M. Kunkel
Keyword(s):  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Muscle Wasting ◽  
Neuromuscular Disorders ◽  
Genetic Diseases ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Progressive Degeneration ◽  
Molecular Pathomechanisms

The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

scholarly journals Lamin A/C–mediated neuromuscular junction defects in Emery-Dreifuss muscular dystrophy

2009 ◽  
Vol 184 (1) ◽  
pp. 31-44 ◽  
Author(s):  
Alexandre Méjat ◽  
Valérie Decostre ◽  
Juan Li ◽  
Laure Renou ◽  
Akanchha Kesari ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Neuromuscular Junctions ◽  
Wide Spectrum ◽  
Nuclear Architecture ◽  
Lamin A ◽  
Cellular Mechanisms ◽  
Activity Dependent ◽  
Filament Type

The LMNA gene encodes lamins A and C, two intermediate filament-type proteins that are important determinants of interphase nuclear architecture. Mutations in LMNA lead to a wide spectrum of human diseases including autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD), which affects skeletal and cardiac muscle. The cellular mechanisms by which mutations in LMNA cause disease have been elusive. Here, we demonstrate that defects in neuromuscular junctions (NMJs) are part of the disease mechanism in AD-EDMD. Two AD-EDMD mouse models show innervation defects including misexpression of electrical activity–dependent genes and altered epigenetic chromatin modifications. Synaptic nuclei are not properly recruited to the NMJ because of mislocalization of nuclear envelope components. AD-EDMD patients with LMNA mutations show the same cellular defects as the AD-EDMD mouse models. These results suggest that lamin A/C–mediated NMJ defects contribute to the AD-EDMD disease phenotype and provide insights into the cellular and molecular mechanisms for the muscle-specific phenotype of AD-EDMD.

scholarly journals Emery-Dreifuss Muscular Dystrophy-Associated Mutant Forms of Lamin A Recruit the Stress Responsive Protein Ankrd2 into the Nucleus, Affecting the Cellular Response to Oxidative Stress

2017 ◽  
Vol 42 (1) ◽  
pp. 169-184 ◽  
Author(s):  
Silvia Angori ◽  
Cristina Capanni ◽  
Georgine Faulkner ◽  
Camilla Bean ◽  
Giuseppe Boriani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Muscular Dystrophy ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Muscle Cells ◽  
Lamin A ◽  
Gene Encoding ◽  
H2o2 Treatment ◽  
Human Myotubes ◽  
Mutant Forms

Background: Ankrd2 is a stress responsive protein mainly expressed in muscle cells. Upon the application of oxidative stress, Ankrd2 translocates into the nucleus where it regulates the activity of genes involved in cellular response to stress. Emery-Dreifuss Muscular Dystrophy 2 (EDMD2) is a muscular disorder caused by mutations of the gene encoding lamin A, LMNA. As well as many phenotypic abnormalities, EDMD2 muscle cells also feature a permanent basal stress state, the underlying molecular mechanisms of which are currently unclear. Methods: Experiments were performed in EDMD2-lamin A overexpressing cell lines and EDMD2-affected human myotubes. Oxidative stress was produced by H2O2 treatment. Co-immunoprecipitation, cellular subfractionation and immunofluorescence analysis were used to validate the relation between Ankrd2 and forms of lamin A; cellular sensibility to stress was monitored by the analysis of Reactive Oxygen Species (ROS) release and cell viability. Results: Our data demonstrate that oxidative stress induces the formation of a complex between Ankrd2 and lamin A. However, EDMD2-lamin A mutants were able to bind and mislocalize Ankrd2 in the nucleus even under basal conditions. Nonetheless, cells co-expressing Ankrd2 and EDMD2-lamin A mutants were more sensitive to oxidative stress than the Ankrd2-wild type lamin A counterpart. Conclusions: For the first time, we present evidence that in muscle fibers from patients affected by EDMD2, Ankrd2 has an unusual nuclear localization. By introducing a plausible mechanism ruling this accumulation, our data hint at a novel function of Ankrd2 in the pathogenesis of EDMD2-affected cells.

scholarly journals Model systems for studying cellular mechanisms of SCN1A-related epilepsy

2016 ◽  
Vol 115 (4) ◽  
pp. 1755-1766 ◽  
Author(s):  
Soleil S. Schutte ◽  
Ryan J. Schutte ◽  
Eden V. Barragan ◽  
Diane K. O'Dowd
Keyword(s):  
Induced Pluripotent Stem Cell ◽  
Febrile Seizures ◽  
Model Systems ◽  
Dravet Syndrome ◽  
Response To Treatment ◽  
Patient Specific ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Induced Pluripotent ◽  
Febrile Seizures Plus

Mutations in SCN1A, the gene encoding voltage-gated sodium channel NaV1.1, cause a spectrum of epilepsy disorders that range from genetic epilepsy with febrile seizures plus to catastrophic disorders such as Dravet syndrome. To date, more than 1,250 mutations in SCN1A have been linked to epilepsy. Distinct effects of individual SCN1A mutations on neuronal function are likely to contribute to variation in disease severity and response to treatment in patients. Several model systems have been used to explore seizure genesis in SCN1A epilepsies. In this article we review what has been learned about cellular mechanisms and potential new therapies from these model systems, with a particular emphasis on the novel model system of knockin Drosophila and a look toward the future with expanded use of patient-specific induced pluripotent stem cell-derived neurons.

scholarly journals The role of mitophagy during oocyte aging in human, mouse and Drosophila; implications for oocyte quality and mitochondrial disease

2021 ◽  
Author(s):  
Rachel T. Cox ◽  
Joanna Poulton ◽  
Suzannah Alice Williams
Keyword(s):  
Molecular Mechanisms ◽  
Assisted Reproductive Technologies ◽  
Reproductive Technologies ◽  
Oocyte Quality ◽  
Model Systems ◽  
Cellular Mechanisms ◽  
Older Mothers ◽  
Mtdna Mutations ◽  
Age Related ◽  
Maternal Aging

There is a worldwide trend for women to have their first pregnancy later in life. However, as oocyte quality declines with maternal aging, this trend leads to an increase in subfertility. The cellular mechanisms underlying this decline in oocyte competence are poorly understood. Oocyte mitochondria are the subcellular organelles that supply the energy that drives early embryogenesis, and thus their quality is critical for successful conception. Mitochondria contain their own DNA (mtDNA) and mutations in mtDNA cause mitochondrial diseases with severe symptoms, such as neurodegeneration and heart disease. Since mitochondrial function declines in tissues as humans age accompanied by an accumulation of mtDNA mutations, mtDNA is implicated as a cause of declining oocyte quality in older mothers. While this mutation load could be caused by declining accuracy of the mitochondrial replisome, age-related decline in mitochondrial quality control likely contributes however knowledge is lacking. Mitophagy, a cellular process which specifically targets and recycles damaged mitochondria, may be involved, but studies are scarce. And although assisted reproductive technologies (ART) can help older mothers, how these techniques affect the mechanisms that regulate mitochondrial and oocyte quality have not been studied. With the long-term goal of understanding the molecular mechanisms that control mitochondrial quality in the oocyte, model systems including Drosophila and mouse as well as human oocytes have been used. In this review we explore the contribution of mitophagy to oocyte quality and the need for further systematic investigation in oocytes during maternal aging using different systems.

scholarly journals MicroRNA role in hereditary genetic diseases

2020 ◽  
pp. 5-17
Author(s):  
О.М. Плотникова ◽  
М.Ю. Скоблов
Keyword(s):  
Gene Expression ◽  
Muscular Dystrophy ◽  
Molecular Mechanisms ◽  
Genetic Diseases ◽  
Hirschsprung Disease ◽  
Facioscapulohumeral Muscular Dystrophy ◽  
Diagnostic Methods ◽  
Hereditary Diseases ◽  
Beta Thalassemia ◽  
Genes Expression

На сегодняшний день известно около 7000 наследственных заболеваний. Однако современные методы ДНК диагностики выявляют причину возникновения заболеваний примерно в 40% случаев. Отчасти это обусловлено сложностью и большим разнообразием молекулярных механизмов их патогенеза. МикроРНК являются одним из мощнейших регуляторов экспрессии генов. Однако участие их в патогенезе наследственных заболеваний пока недостаточно изучено из-за сложностей поиска таких нарушений. В данной работе проведён анализ описанных механизмов патогенеза наследственных заболеваний, опосредованных нарушениями регуляции экспрессии генов посредством микроРНК. Такие случаи были выявлены при таких наследственных заболеваниях как муковисцидоз, миодистрофия Дюшенна, бета-талассемия, глаукома, лице-лопаточно-плечевая миодистрофия Ландузи-Дежерина, болезнь Гиршпрунга, синдром Ретта, синдром Туретта, пемфигус (болезнь Хейли-Хейли). To date, about 7,000 hereditary diseases are known. However, modern diagnostic methods reveal the cause of the disease in about 40% of cases. This is partly due to the complexity and wide variety of molecular mechanisms of pathogenesis. MicroRNAs are one of the most powerful genes expression regulators. But their participation in the pathogenesis of hereditary diseases has not yet been studied enough because of the difficulties in finding such disorders. In this work, we collected and analyzed pathogenesis of hereditary diseases mediated by dysregulation of gene expression by microRNA. such cases have been identified for such hereditary diseases as cystic fibrosis, Duchenne muscular dystrophy, beta-thalassemia, glaucoma, facioscapulohumeral muscular dystrophy Landouzy-Dejerine, Hirschsprung disease, Rett syndrome, Tourette syndrome, pemphigus (Hailey-Hailey disease).

Exercise biology of neuromuscular disorders

2018 ◽  
Vol 43 (11) ◽  
pp. 1194-1206 ◽  
Author(s):  
Sean Y. Ng ◽  
Alexander Manta ◽  
Vladimir Ljubicic
Keyword(s):  
Molecular Mechanisms ◽  
Acute Exercise ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular System ◽  
Cellular Mechanisms ◽  
Disease Mechanisms ◽  
Exercise Adaptation ◽  
Exercise Induced

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular system. Many NMDs currently have no cure; however, as more effective therapies become available for NMD patients, these individuals will exhibit improved health and/or prolonged lifespans. As a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of daily living, including increased physical activity or exercise. Therefore, there is a need to increase our knowledge of the effects of acute exercise and chronic training on the neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and adults. Evidence from clinical and preclinical studies are reviewed, with emphasis on the functional outcomes of exercise, as well as on the putative cellular mechanisms that drive exercise-induced remodelling of the neuromuscular system. Continued investigation of the molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing our understanding of the biology of these most prevalent NMDs. This information may also be useful for guiding the development of novel therapeutic targets for future pursuit.

scholarly journals Evolution of a putative, host-derived endosymbiont division ring and symbiosis-induced proteome rearrangements in the trypanosomatid Angomonas deanei

2021 ◽  
Author(s):  
Jorge Morales ◽  
Georg Ehret ◽  
Gereon Poschmann ◽  
Tobias Reinicke ◽  
Lena Kroeninger ◽  
...  
Keyword(s):  
Host Cell ◽  
Molecular Mechanisms ◽  
Cell Metabolism ◽  
Model Systems ◽  
Gene Encoding ◽  
Endosymbiotic Gene Transfer ◽  
Bacterial Gene ◽  
Protein Mass ◽  
Division Site ◽  
Eukaryote Evolution

The transformation of endosymbiotic bacteria into genetically integrated organelles was central to eukaryote evolution. During organellogenesis, control over endosymbiont division, proteome composition, and physiology largely shifted from the endosymbiont to the host cell nucleus. However, to understand the order and timing of events underpinning organellogenesis novel model systems are required. The trypanosomatid Angomonas deanei contains β-proteobacterial endosymbiont that divides synchronously with the host, contributes essential metabolites to host cell metabolism, and transferred one bacterial gene [encoding an ornithine cyclodeaminase (OCD)] to the nucleus. However, the molecular mechanisms mediating the intricate host/symbiont interactions are largely unexplored. Here we identified seven nucleus-encoded proteins by protein mass spectrometry that are targeted to the endosymbiont. Expression of fluorescent fusion proteins revealed recruitment of these proteins to specific sites within the endosymbiont including its cytoplasm and a ring-shaped structure surrounding its division site. This structure remarkably resembles in shape and predicted functions mitochondrial and plastid division machineries. The endosymbiotic gene transfer-derived OCD localizes to glycosomes instead of being retargeted to the endosymbiont. Hence, scrutiny of protein re-localization patterns that are induced by endosymbiosis, yielded profound insights into how an endosymbiotic relationship can stabilize and deepen over time far beyond the level of metabolite exchange.

scholarly journals Disrupting proteasomal and autophagic degradation systems of misfolded alpha-sarcoglycan protein by bortezomib and givinostat combination

2021 ◽  
Author(s):  
Lucile Hoch ◽  
Nathalie Bourg ◽  
Fanny Degrugillier ◽  
Céline Bruge ◽  
Manon Benabides ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Option ◽  
Genetic Disorder ◽  
Genetic Diseases ◽  
Functional Characterization ◽  
Gene Encoding ◽  
Autophagic Degradation ◽  
Pathway Inhibition ◽  
Shed Light

Background and Purpose: Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. Experimental Approach: We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Key Results: Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Conclusion and Implications: Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.

Electron Microscopy of Fibroblasts from Myotonic Muscular Dystrophy Patients

1981 ◽  
Vol 39 ◽  
pp. 498-499
Author(s):  
S. E. Miller ◽  
G. B. Hartwig ◽  
R. A. Nielsen ◽  
A. P. Frost ◽  
A. D. Roses
Keyword(s):  
Electron Microscopy ◽  
Muscular Dystrophy ◽  
Genetic Diseases ◽  
Skin Fibroblasts ◽  
Inborn Errors ◽  
Cytoplasmic Inclusions ◽  
Cultured Skin ◽  
Myotonic Muscular Dystrophy ◽  
Glycosaminoglycan Metabolism

Many genetic diseases can be demonstrated in skin cells cultured in vitro from patients with inborn errors of metabolism. Since myotonic muscular dystrophy (MMD) affects many organs other than muscle, it seems likely that this defect also might be expressed in fibroblasts. Detection of an alteration in cultured skin fibroblasts from patients would provide a valuable tool in the study of the disease as it would present a readily accessible and controllable system for examination. Furthermore, fibroblast expression would allow diagnosis of fetal and presumptomatic cases. An unusual staining pattern of MMD cultured skin fibroblasts as seen by light microscopy, namely, an increase in alcianophilia and metachromasia, has been reported; both these techniques suggest an altered glycosaminoglycan metabolism An altered growth pattern has also been described. One reference on cultured skin fibroblasts from a different dystrophy (Duchenne Muscular Dystrophy) reports increased cytoplasmic inclusions seen by electron microscopy. Also, ultrastructural alterations have been reported in muscle and thalamus biopsies from MMD patients, but no electron microscopical data is available on MMD cultured skin fibroblasts.

Sign in / Sign up

Export Citation Format

Share Document