scholarly journals The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases

Antioxidants ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 964
Author(s):  
Judith Cantó-Santos ◽  
Josep M. Grau-Junyent ◽  
Glòria Garrabou
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Stress Generation ◽  
Rare Disorders ◽  
Ros Accumulation ◽  
Ros Burst ◽  
The Impact

Neuromuscular diseases (NMDs) are a heterogeneous group of acquired or inherited rare disorders caused by injury or dysfunction of the anterior horn cells of the spinal cord (lower motor neurons), peripheral nerves, neuromuscular junctions, or skeletal muscles leading to muscle weakness and waste. Unfortunately, most of them entail serious or even fatal consequences. The prevalence rates among NMDs range between 1 and 10 per 100,000 population, but their rarity and diversity pose difficulties for healthcare and research. Some molecular hallmarks are being explored to elucidate the mechanisms triggering disease, to set the path for further advances. In fact, in the present review we outline the metabolic alterations of NMDs, mainly focusing on the role of mitochondria. The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction. ROS burst, impaired autophagy, and increased inflammation are observed in many NMDs. Increasing knowledge of the etiology of NMDs will help to develop better diagnosis and treatments, eventually reducing the health and economic burden of NMDs for patients and healthcare systems.

Nimodipine Improves Reinnervation and Neuromuscular Function after Injury to the Recurrent Laryngeal Nerve in the Rat

2007 ◽  
Vol 116 (8) ◽  
pp. 623-630 ◽  
Author(s):  
Jonas Hydman ◽  
Sten Remahl ◽  
Gunnar Björck ◽  
Mikael Svensson ◽  
Per Mattsson
Keyword(s):  
Recurrent Laryngeal Nerve ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neuromuscular Function ◽  
Nerve Fibers ◽  
Laryngeal Nerve ◽  
Crush Injury ◽  
Adult Rats ◽  
Somatotopic Organization ◽  
The Impact

Objectives: Injury of the recurrent laryngeal nerve (RLN) is associated with a high degree of neuronal survival, but leads to various levels of vocal fold motion impairment or laryngeal synkinesis, which has been attributed to misdirected reinnervation of the target muscles in the larynx or aberrant, competing reinnervation from adjacent nerve fibers. The aim of the present study was to evaluate the impact of the regeneration-promoting agent nimodipine on reinnervation and neuromuscular function following RLN crush injury. Methods: Sixty adult rats were randomized into nimodipine-treated or untreated groups and then underwent RLN crush injury. Reinnervation of the posterior cricoarytenoid muscle (PCA) was assessed by electrophysiological examination, retrograde tracing of lower motor neurons before and after injury, and quantification of neuromuscular junctions in the PCA muscle. Results: At 6 weeks after injury, the nimodipine-treated animals showed significantly enhanced neuromuscular function and also demonstrated a higher number of motor neurons in the brain stem that had reinnervated the PCA, compared to the untreated animals. The somatotopic organization of ambiguus motor neurons innervating the larynx was similar before injury and after reinnervation. Conclusions: Nimodipine improves regeneration and neuromuscular function following RLN injury in the adult rat, and could be of use in future strategies following RLN injury.

scholarly journals SOD1 Gene Silencing Promotes Apoptosis and Suppresses Proliferation of Heat-Stressed Bovine Granulosa Cells via Induction of Oxidative Stress

2021 ◽  
Vol 8 (12) ◽  
pp. 326
Author(s):  
Adnan Khan ◽  
Muhammad Zahoor Khan ◽  
Jinhuan Dou ◽  
Huitao Xu ◽  
Lei Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Oxidative Damage ◽  
Granulosa Cells ◽  
Sod1 Gene ◽  
Hormone Synthesis ◽  
Ros Accumulation ◽  
Proliferation And Apoptosis ◽  
Cattle Reproduction ◽  
The Impact

Heat stress (HS) compromises dairy cattle reproduction by altering the follicular dynamics, oocyte maturation, and normal physiological function of ovarian granulosa cells (GCs), eventually resulting in oxidative damage and cell apoptosis. To protect the cells from oxidative damage, the Superoxide dismutase-1 (SOD1) degraded the hydrogen peroxide (H2O2) to oxygen (O2) and water. The objective of the current study was to investigate the impact of SOD1 silencing on intracellular ROS accumulation, cell viability, MMP, hormone synthesis (P4, E2), cell proliferation, and apoptosis in GCs under HS. The mechanistic role of SOD1 regulation in the heat-stressed GCs was explored. SOD1 gene was successfully silenced in GCs and confirmed at both transcriptional and translational levels. We found that silencing of SOD1 using siRNA under HS aggravated intracellular accumulation of reactive oxygen species, apoptosis, disrupted the mitochondrial membrane potential (MMP), altered transition of the cell cycle, and impaired synthesis of progesterone (P4) and estrogen (E2) in GCs. The associative apoptotic, steroidogenic, and cell cycle genes (BAX, Caspase-3, STAR, Cyp11A1, HSP70, PCNA, and CyclinB1) were used to confirm the results. These results identify a novel role of SOD1 in the modulation of bovine ovarian GC apoptosis, which provides a target for improving the fertility of heat-stressed dairy cows in summer.

An ALS-associated mutation in human FUS reduces neurotransmission from C. elegans motor neurons to muscles

2019 ◽  
Author(s):  
Sebastian M. Markert ◽  
Michael Skoruppa ◽  
Bin Yu ◽  
Ben Mulcahy ◽  
Mei Zhen ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Electron Tomography ◽  
Light And Electron Microscopy ◽  
Electrophysiological Recording ◽  
C Elegans ◽  
Fused In Sarcoma ◽  
And Function ◽  
The Impact

AbstractAmytrophic lateral sclerosis (ALS) is a neurodegenerative disorder that has been associated with multiple genetic lesions, including mutations in the gene FUS (Fused in Sarcoma), an RNA/DNA-binding protein. Expression of the ALS-associated human FUS in C. elegans results in mislocalization and aggregation of FUS outside the nucleus, and leads to impaired neuromuscular behaviors. However, the mechanisms by which mutant FUS disrupts neuronal health and function remain partially understood. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. Expression of ALS-associated FUS impairs synaptic vesicle docking at neuromuscular junctions, and leads to the emergence of a population of large and electron-dense filament-filled endosomes. Electrophysiological recording of neuromuscular transmission revealed reduced transmission from motor neurons to muscles. Together, these results suggest a potential direct or indirect role of human FUS in the organization of synaptic vesicles, and reduced transmission from motor neurons to muscles.Summary statementAn ALS-associated mutation in a trafficking protein disrupts the organization of the C. elegans neuromuscular junction.

scholarly journals Cul4 ubiquitin ligase cofactor DCAF12 promotes neurotransmitter release and homeostatic plasticity

2019 ◽  
Vol 218 (3) ◽  
pp. 993-1010 ◽  
Author(s):  
Lilian A. Patrón ◽  
Kei Nagatomo ◽  
David Tyler Eves ◽  
Mays Imad ◽  
Kimberly Young ◽  
...  
Keyword(s):  
Glutamate Receptor ◽  
Motor Neurons ◽  
Ubiquitin Ligase ◽  
Neurotransmitter Release ◽  
Neuromuscular Junctions ◽  
Synaptic Function ◽  
Homeostatic Plasticity ◽  
Independent Functions ◽  
Synaptic Boutons

We genetically characterized the synaptic role of the Drosophila homologue of human DCAF12, a putative cofactor of Cullin4 (Cul4) ubiquitin ligase complexes. Deletion of Drosophila DCAF12 impairs larval locomotion and arrests development. At larval neuromuscular junctions (NMJs), DCAF12 is expressed presynaptically in synaptic boutons, axons, and nuclei of motor neurons. Postsynaptically, DCAF12 is expressed in muscle nuclei and facilitates Cul4-dependent ubiquitination. Genetic experiments identified several mechanistically independent functions of DCAF12 at larval NMJs. First, presynaptic DCAF12 promotes evoked neurotransmitter release. Second, postsynaptic DCAF12 negatively controls the synaptic levels of the glutamate receptor subunits GluRIIA, GluRIIC, and GluRIID. The down-regulation of synaptic GluRIIA subunits by nuclear DCAF12 requires Cul4. Third, presynaptic DCAF12 is required for the expression of synaptic homeostatic potentiation. We suggest that DCAF12 and Cul4 are critical for normal synaptic function and plasticity at larval NMJs.

scholarly journals Overexpression of an ALS-associated FUS mutation in C. elegans disrupts NMJ morphology and leads to defective neuromuscular transmission

Biology Open ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. bio055129 ◽  
Author(s):  
Sebastian M. Markert ◽  
Michael Skoruppa ◽  
Bin Yu ◽  
Ben Mulcahy ◽  
Mei Zhen ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Electron Tomography ◽  
Light And Electron Microscopy ◽  
Ectopic Expression ◽  
Electrophysiological Recording ◽  
Pathological Effect ◽  
And Function ◽  
The Impact

ABSTRACTThe amyotrophic lateral sclerosis (ALS) neurodegenerative disorder has been associated with multiple genetic lesions, including mutations in the gene for fused in sarcoma (FUS), a nuclear-localized RNA/DNA-binding protein. Neuronal expression of the pathological form of FUS proteins in Caenorhabditis elegans results in mislocalization and aggregation of FUS in the cytoplasm, and leads to impairment of motility. However, the mechanisms by which the mutant FUS disrupts neuronal health and function remain unclear. Here we investigated the impact of ALS-associated FUS on motor neuron health using correlative light and electron microscopy, electron tomography, and electrophysiology. We show that ectopic expression of wild-type or ALS-associated human FUS impairs synaptic vesicle docking at neuromuscular junctions. ALS-associated FUS led to the emergence of a population of large, electron-dense, and filament-filled endosomes. Electrophysiological recording revealed reduced transmission from motor neurons to muscles. Together, these results suggest a pathological effect of ALS-causing FUS at synaptic structure and function organization.This article has an associated First Person interview with the first author of the paper.

Antibodies Against Cysteine String Proteins Inhibit Evoked Neurotransmitter Release at Xenopus Neuromuscular Junctions

1999 ◽  
Vol 82 (1) ◽  
pp. 50-59 ◽  
Author(s):  
Robert E. Poage ◽  
Stephen D. Meriney ◽  
Cameron B. Gundersen ◽  
Joy A. Umbach
Keyword(s):  
Motor Neurons ◽  
Neurotransmitter Release ◽  
Neuromuscular Junctions ◽  
Selective Inhibition ◽  
Spinal Motor Neurons ◽  
Neurotransmitter Secretion ◽  
Spinal Motor ◽  
Evolutionarily Conserved ◽  
Antibody Effects

Cysteine string proteins (CSPs) are evolutionarily conserved proteins that are associated with synaptic vesicles and other regulated secretory organelles. To investigate the role of CSPs in vertebrate neuromuscular transmission, we introduced anti-CSP antibodies into the cell bodies of Xenopus spinal motor neurons that form synapses with embryonic muscle cells in culture. These antibodies produced a rapid (within 3–6 min), and in most cases complete, inhibition of stimulus-dependent neurotransmitter secretion. However, spontaneous neurotransmitter release was stable (both in frequency and amplitude) throughout the period of antibody exposure. Several control experiments validated the specificity of the anti-CSP antibody effects. First, the anti-CSP antibody actions were not mimicked either by antibodies against another synaptic vesicle protein SV2, or by nonspecific immunoglobins. Second, heat treatment of the anti-CSP antibodies eliminated their effect on evoked secretion. Third, immunoblot experiments showed that the anti-CSP and anti-SV2 antibodies were highly selective for their respective antigens in these Xenopus cultures. We conclude from these results that CSPs are vital constituents of the pathway for regulated neurotransmitter release in vertebrates. Moreover, the selective inhibition of evoked, but not spontaneous transmitter release by anti-CSP antibodies indicates that there is a fundamental difference in the machinery that mediates these secretory processes.

scholarly journals Effect of ALS IgG on Motor Neurons in Organotypic Spinal Cord Cultures

2008 ◽  
Vol 35 (2) ◽  
pp. 220-225 ◽  
Author(s):  
Bin Li ◽  
Xiao-Yun Liu ◽  
Zhe Li ◽  
Hui Bu ◽  
Meng-Meng Sun ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Lactate Dehydrogenase ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Culture Medium ◽  
Long Term Treatment ◽  
Significant Difference ◽  
Als Patients ◽  
The Impact

Objective:Reports about the role of autoimmunity in amyotrophic lateral sclerosis (ALS) are inconsistent. The aim of this work was to investigate the effect of IgG from patients with ALS on motor neurons in a physiological-like surrounding.Methods:Using affinity chromatography, IgG from six ALS patients, four disease controls and five healthy subjects was purified. Organotypic spinal cord cultures, which conserve the structure of the spinal cord in a horizontal plane and are suitable for studies with long-term treatment, were used and IgG with different concentrations ranging from 0.05 mg/mL to 0.5 mg/mL was added to the culture medium. Ventral motor neuron survival was evaluated by morphology and SMI-32 immunohistochemistry staining. Lactate dehydrogenase (LDH) level in the culture medium was measured by colorimetry.Results:After cultures were treated with ALS IgG for three weeks, the number and morphology of motor neurons showed little change. In addition, there was no significant difference in lactate dehydrogenase release between cultures treated with medium alone, normal control IgG, disease control IgG or ALS IgG.Conclusions:The results indicate that IgG from these ALS patients was insufficient per se to induce motor neuron death in Organotypic slice cultures. However, this does not preclude the possibility that other changes may have occurred in the motor neurons. This work offered a new model to evaluate the role of IgG in the pathogenesis of ALS. Organotypic cultures contribute to study of the impact of IgG on motor neurons by mimicking physiological conditions.

Intergroup Threat and Outgroup Attitudes

2013 ◽  
Vol 44 (5) ◽  
pp. 311-319 ◽  
Author(s):  
Marco Brambilla ◽  
David A. Butz
Keyword(s):  
Gay Men ◽  
Social Group ◽  
Welfare Recipients ◽  
Intergroup Attitudes ◽  
Social Policies ◽  
Intergroup Threat ◽  
Economic Threat ◽  
The Impact ◽  
General Climate

Two studies examined the impact of macrolevel symbolic threat on intergroup attitudes. In Study 1 (N = 71), participants exposed to a macrosymbolic threat (vs. nonsymbolic threat and neutral topic) reported less support toward social policies concerning gay men, an outgroup whose stereotypes implies a threat to values, but not toward welfare recipients, a social group whose stereotypes do not imply a threat to values. Study 2 (N = 78) showed that, whereas macrolevel symbolic threat led to less favorable attitudes toward gay men, macroeconomic threat led to less favorable attitudes toward Asians, an outgroup whose stereotypes imply an economic threat. These findings are discussed in terms of their implications for understanding the role of a general climate of threat in shaping intergroup attitudes.

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