scholarly journals The Ubiquitin Proteasome System in Neuromuscular Disorders: Moving Beyond Movement

2020 ◽  
Vol 21 (17) ◽  
pp. 6429 ◽  
Author(s):  
Sara Bachiller ◽  
Isabel M. Alonso-Bellido ◽  
Luis Miguel Real ◽  
Eva María Pérez-Villegas ◽  
José Luis Venero ◽  
...  
Keyword(s):  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Ubiquitin Proteasome System ◽  
Neuromuscular Disorder ◽  
Enzymatic Reactions ◽  
Protein Homeostasis ◽  
Motor Neuron Diseases ◽  
Charcot Marie Tooth Disease ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome

Neuromuscular disorders (NMDs) affect 1 in 3000 people worldwide. There are more than 150 different types of NMDs, where the common feature is the loss of muscle strength. These disorders are classified according to their neuroanatomical location, as motor neuron diseases, peripheral nerve diseases, neuromuscular junction diseases, and muscle diseases. Over the years, numerous studies have pointed to protein homeostasis as a crucial factor in the development of these fatal diseases. The ubiquitin–proteasome system (UPS) plays a fundamental role in maintaining protein homeostasis, being involved in protein degradation, among other cellular functions. Through a cascade of enzymatic reactions, proteins are ubiquitinated, tagged, and translocated to the proteasome to be degraded. Within the ubiquitin system, we can find three main groups of enzymes: E1 (ubiquitin-activating enzymes), E2 (ubiquitin-conjugating enzymes), and E3 (ubiquitin–protein ligases). Only the ubiquitinated proteins with specific chain linkages (such as K48) will be degraded by the UPS. In this review, we describe the relevance of this system in NMDs, summarizing the UPS proteins that have been involved in pathological conditions and neuromuscular disorders, such as Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), or Duchenne Muscular Dystrophy (DMD), among others. A better knowledge of the processes involved in the maintenance of proteostasis may pave the way for future progress in neuromuscular disorder studies and treatments.

SMN complexes of nucleus and cytoplasm: A proteomic study for SMA therapy

2010 ◽  
Vol 1 (4) ◽  
Author(s):  
Heidi Fuller ◽  
Glenn Morris
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Ubiquitin Proteasome System ◽  
Neuromuscular Disorder ◽  
Nuclear Extracts ◽  
Smn Complex ◽  
Proteomic Study ◽  
Ubiquitin Proteasome ◽  
Survival Of Motor Neurons ◽  
Smn Protein

AbstractReduced levels of the survival of motor neurons protein (SMN), cause the inherited neuromuscular disorder, spinal muscular atrophy (SMA). The majority of therapeutic approaches to date have been focused on finding ways to increase expression of functional SMN protein, though stabilization of SMN protein may also be an important consideration. SMN interacts, directly or indirectly, stably or transiently, with a large number of other proteins, some of which contribute to SMN stability and may therefore be potential targets for SMA therapy. We recently characterized the nuclear SMN interactome using LC-MALDI-TOF/TOF analysis of anti-SMN pull-downs and identified myb-binding protein-1a (Mybbp1a) as a novel partner. In light of interest in cytoplasm-specific roles of the SMN complex, we have applied the same approach to characterise the cytoplasmic SMN interactome. We now show that SMN complexes from HeLa cytoplasmic extracts differ significantly from those found in nuclear extracts, with gemin5, importinbeta and annexin A2 easily detected only in the cytoplasmic extracts, whereas interaction of SMN with Mybbp1a appears to occur only in the nucleus. SMN is ubiquitinylated and we also found proteins of the ubiquitin-proteasome system associated with SMN in the cytoplasm.

scholarly journals A 20-year Clinical and Genetic Neuromuscular Cohort Analysis in Lebanon: An International Effort

2021 ◽  
pp. 1-18
Author(s):  
Andre Megarbane ◽  
Sami Bizzari ◽  
Asha Deepthi ◽  
Sandra Sabbagh ◽  
Hicham Mansour ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Cohort Analysis ◽  
Becker Muscular Dystrophy ◽  
Molecular Data ◽  
Motor Neuron Diseases ◽  
Charcot Marie Tooth Disease ◽  
High Prevalence ◽  
Tooth Disease

Background: Clinical and molecular data on the occurrence and frequency of inherited neuromuscular disorders (NMD) in the Lebanese population is scarce. Objective: This study aims to provide a retrospective overview of hereditary NMDs based on our clinical consultations in Lebanon. Methods: Clinical and molecular data of patients referred to a multi-disciplinary consultation for neuromuscular disorders over a 20-year period (1999–2019) was reviewed. Results: A total of 506 patients were diagnosed with 62 different disorders encompassing 10 classes of NMDs. 103 variants in 49 genes were identified. In this cohort, 81.4%of patients were diagnosed with motor neuron diseases and muscular dystrophies, with almost half of these described with spinal muscular atrophy (SMA) (40.3%of patients). We estimate a high SMA incidence of 1 in 7,500 births in Lebanon. Duchenne and Becker muscular dystrophy were the second most frequently diagnosed NMDs (17%of patients). The latter disorders were associated with the highest number of variants (39) identified in this study. A highly heterogeneous presentation of Limb Girdle Muscular Dystrophy and Charcot-Marie-Tooth disease was notably identified. The least common disorders (5.5%of patients) involved congenital, metabolic, and mitochondrial myopathies, congenital myasthenic syndromes, and myotonic dystrophies. A review of the literature for selected NMDs in Lebanon is provided. Conclusions: Our study indicates a high prevalence and underreporting of heterogeneous forms of NMDs in Lebanon- a major challenge with many novel NMD treatments in the pipeline. This report calls for a regional NMD patient registry.

scholarly journals Immunoproteasome Function in Normal and Malignant Hematopoiesis

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1577
Author(s):  
Nuria Tubío-Santamaría ◽  
Frédéric Ebstein ◽  
Florian H. Heidel ◽  
Elke Krüger
Keyword(s):  
Proteasome Inhibition ◽  
Ubiquitin Proteasome System ◽  
Hematologic Malignancies ◽  
Protein Homeostasis ◽  
Efficacy And Safety ◽  
Hematopoietic System ◽  
Oxidized Proteins ◽  
Attractive Therapeutic Target ◽  
Ubiquitin Proteasome ◽  
Early Phases

The ubiquitin–proteasome system (UPS) is a central part of protein homeostasis, degrading not only misfolded or oxidized proteins but also proteins with essential functions. The fact that a healthy hematopoietic system relies on the regulation of protein homeostasis and that alterations in the UPS can lead to malignant transformation makes the UPS an attractive therapeutic target for the treatment of hematologic malignancies. Herein, inhibitors of the proteasome, the last and most important component of the UPS enzymatic cascade, have been approved for the treatment of these malignancies. However, their use has been associated with side effects, drug resistance, and relapse. Inhibitors of the immunoproteasome, a proteasomal variant constitutively expressed in the cells of hematopoietic origin, could potentially overcome the encountered problems of non-selective proteasome inhibition. Immunoproteasome inhibitors have demonstrated their efficacy and safety against inflammatory and autoimmune diseases, even though their development for the treatment of hematologic malignancies is still in the early phases. Various immunoproteasome inhibitors have shown promising preliminary results in pre-clinical studies, and one inhibitor is currently being investigated in clinical trials for the treatment of multiple myeloma. Here, we will review data on immunoproteasome function and inhibition in hematopoietic cells and hematologic cancers.

scholarly journals A Homeostatic Shift Facilitates Endoplasmic Reticulum Proteostasis through Transcriptional Integration of Proteostatic Stress Response Pathways

2016 ◽  
Vol 37 (4) ◽  
Author(s):  
Liam Baird ◽  
Tadayuki Tsujita ◽  
Eri H. Kobayashi ◽  
Ryo Funayama ◽  
Takeshi Nagashima ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcriptional Regulation ◽  
Ubiquitin Proteasome System ◽  
Conditional Knockout ◽  
Protein Homeostasis ◽  
Knockout Mouse Model ◽  
Conditional Knockout Mouse ◽  
Wide Range ◽  
Ubiquitin Proteasome ◽  
Inducible Systems

ABSTRACT Eukaryotic cells maintain protein homeostasis through the activity of multiple basal and inducible systems, which function in concert to allow cells to adapt to a wide range of environmental conditions. Although the transcriptional programs regulating individual pathways have been studied in detail, it is not known how the different pathways are transcriptionally integrated such that a deficiency in one pathway can be compensated by a change in an auxiliary response. One such pathway that plays an essential role in many proteostasis responses is the ubiquitin-proteasome system, which functions to degrade damaged, unfolded, or short half-life proteins. Transcriptional regulation of the proteasome is mediated by the transcription factor Nrf1. Using a conditional knockout mouse model, we found that Nrf1 regulates protein homeostasis in the endoplasmic reticulum (ER) through transcriptional regulation of the ER stress sensor ATF6. In Nrf1 conditional-knockout mice, a reduction in proteasome activity is accompanied by an ATF6-dependent downregulation of the endoplasmic reticulum-associated degradation machinery, which reduces the substrate burden on the proteasome. This indicates that Nrf1 regulates a homeostatic shift through which proteostasis in the endoplasmic reticulum and cytoplasm are coregulated based on a cell's ability to degrade proteins.

scholarly journals Molecular Chaperones and Proteolytic Machineries Regulate Protein Homeostasis in Aging Cells

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1308 ◽  
Author(s):  
Boris Margulis ◽  
Anna Tsimokha ◽  
Svetlana Zubova ◽  
Irina Guzhova
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Molecular Chaperones ◽  
Ubiquitin Proteasome System ◽  
Life Cycles ◽  
Protein Homeostasis ◽  
Ubiquitin Proteasome ◽  
Correct Function ◽  
Regulate Protein

Throughout their life cycles, cells are subject to a variety of stresses that lead to a compromise between cell death and survival. Survival is partially provided by the cell proteostasis network, which consists of molecular chaperones, a ubiquitin-proteasome system of degradation and autophagy. The cooperation of these systems impacts the correct function of protein synthesis/modification/transport machinery starting from the adaption of nascent polypeptides to cellular overcrowding until the utilization of damaged or needless proteins. Eventually, aging cells, in parallel to the accumulation of flawed proteins, gradually lose their proteostasis mechanisms, and this loss leads to the degeneration of large cellular masses and to number of age-associated pathologies and ultimately death. In this review, we describe the function of proteostasis mechanisms with an emphasis on the possible associations between them.

Epigenetics of neuromuscular disorders

Epigenomics ◽  
2020 ◽  
Vol 12 (23) ◽  
pp. 2125-2139
Author(s):  
Fabio Coppedè
Keyword(s):  
Dna Methylation ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Motor Neuron Diseases ◽  
Disease Biomarkers ◽  
Prognostic Accuracy ◽  
Epigenetic Biomarkers ◽  
Mutational Screening ◽  
Culture Models ◽  
Near Future

Neuromuscular disorders are a heterogeneous group of conditions affecting the neuromuscular system. The aim of this article is to review the major epigenetic findings in motor neuron diseases and major hereditary muscular dystrophies. DNA methylation changes are observed in both hereditary and sporadic forms, and combining DNA methylation analysis with mutational screening holds the potential for better diagnostic and prognostic accuracy. Novel, less toxic and more selective epigenetic drugs are designed and tested in animal and cell culture models of neuromuscular disorders, and non-coding RNAs are being investigated as either disease biomarkers or targets of therapeutic approaches to restore gene expression levels. Overall, neuromuscular disorder epigenetic biomarkers have a strong potential for clinical applications in the near future.

scholarly journals Of rAAV and Men: From Genetic Neuromuscular Disorder Efficacy and Toxicity Preclinical Studies to Clinical Trials and Back

2020 ◽  
Vol 10 (4) ◽  
pp. 258
Author(s):  
Laurine Buscara ◽  
David-Alexandre Gross ◽  
Nathalie Daniele
Keyword(s):  
Clinical Trials ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Whole Body ◽  
Skeletal Muscle Atrophy ◽  
General Strategy ◽  
Serious Adverse Events ◽  
Worst Case ◽  
Organ Failures

Neuromuscular disorders are a large group of rare pathologies characterised by skeletal muscle atrophy and weakness, with the common involvement of respiratory and/or cardiac muscles. These diseases lead to life-long motor deficiencies and specific organ failures, and are, in their worst-case scenarios, life threatening. Amongst other causes, they can be genetically inherited through mutations in more than 500 different genes. In the last 20 years, specific pharmacological treatments have been approved for human usage. However, these “à-la-carte” therapies cover only a very small portion of the clinical needs and are often partially efficient in alleviating the symptoms of the disease, even less so in curing it. Recombinant adeno-associated virus vector-mediated gene transfer is a more general strategy that could be adapted for a large majority of these diseases and has proved very efficient in rescuing the symptoms in many neuropathological animal models. On this solid ground, several clinical trials are currently being conducted with the whole-body delivery of the therapeutic vectors. This review recapitulates the state-of-the-art tools for neuron and muscle-targeted gene therapy, and summarises the main findings of the spinal muscular atrophy (SMA), Duchenne muscular dystrophy (DMD) and X-linked myotubular myopathy (XLMTM) trials. Despite promising efficacy results, serious adverse events of various severities were observed in these trials. Possible leads for second-generation products are also discussed.

scholarly journals Regulation of β-Catenin Levels and Localization by Overexpression of Plakoglobin and Inhibition of the Ubiquitin-Proteasome System

1997 ◽  
Vol 139 (5) ◽  
pp. 1325-1335 ◽  
Author(s):  
Daniela Salomon ◽  
Paula A. Sacco ◽  
Sujata Guha Roy ◽  
Inbal Simcha ◽  
Keith R. Johnson ◽  
...  
Keyword(s):  
Adherens Junctions ◽  
Ubiquitin Proteasome System ◽  
Binding Domain ◽  
Cell Junctions ◽  
Stable Transfection ◽  
Desmosomal Cadherins ◽  
Ubiquitin System ◽  
Ubiquitin Proteasome ◽  
Dose Dependent Decrease ◽  
Cell Cell

β-Catenin and plakoglobin (γ-catenin) are closely related molecules of the armadillo family of proteins. They are localized at the submembrane plaques of cell–cell adherens junctions where they form independent complexes with classical cadherins and α-catenin to establish the link with the actin cytoskeleton. Plakoglobin is also found in a complex with desmosomal cadherins and is involved in anchoring intermediate filaments to desmosomal plaques. In addition to their role in junctional assembly, β-catenin has been shown to play an essential role in signal transduction by the Wnt pathway that results in its translocation into the nucleus. To study the relationship between plakoglobin expression and the level of β-catenin, and the localization of these proteins in the same cell, we employed two different tumor cell lines that express N-cadherin, and α- and β-catenin, but no plakoglobin or desmosomal components. Individual clones expressing various levels of plakoglobin were established by stable transfection. Plakoglobin overexpression resulted in a dose-dependent decrease in the level of β-catenin in each clone. Induction of plakoglobin expression increased the turnover of β-catenin without affecting RNA levels, suggesting posttranslational regulation of β-catenin. In plakoglobin overexpressing cells, both β-catenin and plakoglobin were localized at cell– cell junctions. Stable transfection of mutant plakoglobin molecules showed that deletion of the N-cadherin binding domain, but not the α-catenin binding domain, abolished β-catenin downregulation. Inhibition of the ubiquitin-proteasome pathway in plakoglobin overexpressing cells blocked the decrease in β-catenin levels and resulted in accumulation of both β-catenin and plakoglobin in the nucleus. These results suggest that (a) plakoglobin substitutes effectively with β-catenin for association with N-cadherin in adherens junctions, (b) extrajunctional β-catenin is rapidly degraded by the proteasome-ubiquitin system but, (c) excess β-catenin and plakoglobin translocate into the nucleus.

scholarly journals Obstetric-Gynecological Complications in Neuromuscular Disorders

2020 ◽  
Vol 1 (3) ◽  
pp. 5-8
Author(s):  
Lakshmi Digala ◽  
Zahra Haider ◽  
Raghav Govindarajan
Keyword(s):  
Neuromuscular Disease ◽  
Muscular Atrophy ◽  
Case Reports ◽  
Neuromuscular Disorders ◽  
Neuromuscular Diseases ◽  
Retrospective Chart Review ◽  
Obstetric Complications ◽  
University Of Missouri ◽  
Charcot Marie Tooth Disease ◽  
One Year

Background and Objective: The data on the obstetric and gynecological complications in patients diagnosed with neuromuscular diseases is very limited and is primarily obtained from various case reports, series, and small studies.  The objective of our study was to analyze the prevalence of these complications in a large cohort of patients with various neuromuscular diseases. Methods: This study is a retrospective chart review of patients diagnosed with various neuromuscular diseases at the University of Missouri, Columbia, from 2012 to 2017. We included patients who have at least one year follow up with us. We collected data on patient demographics, neuromuscular disease diagnosed, obstetric complications, and gynecologic complications. Data are reported as means ± SEM, and the results reported using prevalence rates. Results: Ninety-five female patients were identified. Among them, 97% were Caucasian, and 3% were African-American with a mean age of 47.96 years.  Neuromuscular diseases identified among them are Myasthenia Gravis (44%), Muscular Dystrophy (23%), Amyotrophic Lateral Sclerosis-ALS (16%), Charcot-Marie-Tooth disease-CMT (10%), and Spinal Muscular atrophy- SMA (7%). The majority of the patients reviewed have had no obstetric complications- (89.40%). The most common obstetric complication recorded was C-section (8.40%).  41% of women did not have any gynecological complaints. Urine incontinence (24.20%) is the most common complication. Conclusion: C-sections and urinary incontinence are common obstetric and gynecological events seen in women with neuromuscular disease.

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