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.

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 Myomirnas Role in Als Suggest a Crosstalk between Muscle and Motor Neuron

2018 ◽  
Author(s):  
Valentina Pegoraro ◽  
Antonio Merico ◽  
Corrado Angelini
Keyword(s):  
Skeletal Muscle ◽  
Motor Neuron ◽  
Aerobic Exercise ◽  
Muscle Atrophy ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Muscle Fibres ◽  
Wide Range

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads from lower motor neuron involvement to progressive muscle atrophy, weakness, fasciculations for the upper motor neuron involvement to spasticity. Muscle atrophy in ALS is caused by a dysregulation in the molecular network controlling fast and slow muscle fibres. Denervation and reinnervation processes in skeletal muscle occur in the course of ALS and are modulated by rehabilitation. MicroRNAs (miRNAs) are small non-coding RNAs that modulate a wide range of biological functions under various pathophysiological conditions. MiRNAs can be secreted by various cell types and they are markedly stable in body fluids. MiR-1, miR-133 a, miR-133b, and miR-206 are called “myomiRs” and are considered markers of myogenesis during muscle regeneration and neuromuscular junction stabilization or sprouting. We observed a positive effect of a standard aerobic exercise rehabilitative protocol conducted for six weeks in 18 ALS patients during hospitalization in our center. We correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, myomiRNAs were down-regulated, suggesting an active proliferation of satellite cells in muscle and increased neuromuscular junctions. Our data suggest that circulating miRNAs modulate during skeletal muscle recovery in response to physical rehabilitation in ALS.

scholarly journals Neuronal over-expression of Oxr1 is protective against ALS-associated mutant TDP-43 mislocalisation in motor neurons and neuromuscular defects in vivo

2019 ◽  
Vol 28 (21) ◽  
pp. 3584-3599 ◽  
Author(s):  
Matthew G Williamson ◽  
Mattéa J Finelli ◽  
James N Sleigh ◽  
Amy Reddington ◽  
David Gordon ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Gene Encoding ◽  
Over Expression ◽  
Neuromuscular Abnormalities ◽  
And Function ◽  
Lateral Sclerosis

Abstract A common pathological hallmark of amyotrophic lateral sclerosis (ALS) and the related neurodegenerative disorder frontotemporal dementia, is the cellular mislocalization of transactive response DNA-binding protein 43 kDa (TDP-43). Additionally, multiple mutations in the TARDBP gene (encoding TDP-43) are associated with familial forms of ALS. While the exact role for TDP-43 in the onset and progression of ALS remains unclear, the identification of factors that can prevent aberrant TDP-43 localization and function could be clinically beneficial. Previously, we discovered that the oxidation resistance 1 (Oxr1) protein could alleviate cellular mislocalization phenotypes associated with TDP-43 mutations, and that over-expression of Oxr1 was able to delay neuromuscular abnormalities in the hSOD1G93A ALS mouse model. Here, to determine whether Oxr1 can protect against TDP-43-associated phenotypes in vitro and in vivo, we used the same genetic approach in a newly described transgenic mouse expressing the human TDP-43 locus harbouring an ALS disease mutation (TDP-43M337V). We show in primary motor neurons from TDP-43M337V mice that genetically-driven Oxr1 over-expression significantly alleviates cytoplasmic mislocalization of mutant TDP-43. We also further quantified newly-identified, late-onset neuromuscular phenotypes of this mutant line, and demonstrate that neuronal Oxr1 over-expression causes a significant reduction in muscle denervation and neuromuscular junction degeneration in homozygous mutants in parallel with improved motor function and a reduction in neuroinflammation. Together these data support the application of Oxr1 as a viable and safe modifier of TDP-43-associated ALS phenotypes.

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 Personal Perspectives on Plant Ribosomal RNA Genes Research: From Precursor-rRNA to Molecular Evolution

2021 ◽  
Vol 12 ◽  
Author(s):  
Vera Hemleben ◽  
Donald Grierson ◽  
Nikolai Borisjuk ◽  
Roman A. Volkov ◽  
Ales Kovarik
Keyword(s):  
Organizer Region ◽  
Nucleolar Organizer Region ◽  
Light And Electron Microscopy ◽  
Scientific Progress ◽  
5S Rdna ◽  
Molecular Organization ◽  
Rrna Genes ◽  
Detailed Knowledge ◽  
And Function ◽  
The Impact

The history of rDNA research started almost 90 years ago when the geneticist, Barbara McClintock observed that in interphase nuclei of maize the nucleolus was formed in association with a specific region normally located near the end of a chromosome, which she called the nucleolar organizer region (NOR). Cytologists in the twentieth century recognized the nucleolus as a common structure in all eukaryotic cells, using both light and electron microscopy and biochemical and genetic studies identified ribosomes as the subcellular sites of protein synthesis. In the mid- to late 1960s, the synthesis of nuclear-encoded rRNA was the only system in multicellular organisms where transcripts of known function could be isolated, and their synthesis and processing could be studied. Cytogenetic observations of NOR regions with altered structure in plant interspecific hybrids and detailed knowledge of structure and function of rDNA were prerequisites for studies of nucleolar dominance, epistatic interactions of rDNA loci, and epigenetic silencing. In this article, we focus on the early rDNA research in plants, performed mainly at the dawn of molecular biology in the 60 to 80-ties of the last century which presented a prequel to the modern genomic era. We discuss – from a personal view – the topics such as synthesis of rRNA precursor (35S pre-rRNA in plants), processing, and the organization of 35S and 5S rDNA. Cloning and sequencing led to the observation that the transcribed and processed regions of the rRNA genes vary enormously, even between populations and species, in comparison with the more conserved regions coding for the mature rRNAs. Epigenetic phenomena and the impact of hybridization and allopolyploidy on rDNA expression and homogenization are discussed. This historical view of scientific progress and achievements sets the scene for the other articles highlighting the immense progress in rDNA research published in this special issue of Frontiers in Plant Science on “Molecular organization, evolution, and function of ribosomal DNA.”

scholarly journals Sympathetic innervation controls homeostasis of neuromuscular junctions in health and disease

2016 ◽  
Vol 113 (3) ◽  
pp. 746-750 ◽  
Author(s):  
Muzamil Majid Khan ◽  
Danilo Lustrino ◽  
Willian A. Silveira ◽  
Franziska Wild ◽  
Tatjana Straka ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Close Contact ◽  
Sympathetic Neurons ◽  
Sympathetic Innervation ◽  
Peroxisome Proliferator ◽  
Direct Stimulation ◽  
Peroxisome Proliferator Activated Receptor ◽  
And Function

The distribution and function of sympathetic innervation in skeletal muscle have largely remained elusive. Here we demonstrate that sympathetic neurons make close contact with neuromuscular junctions and form a network in skeletal muscle that may functionally couple different targets including blood vessels, motor neurons, and muscle fibers. Direct stimulation of sympathetic neurons led to activation of muscle postsynaptic β2-adrenoreceptor (ADRB2), cAMP production, and import of the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PPARGC1A) into myonuclei. Electrophysiological and morphological deficits of neuromuscular junctions upon sympathectomy and in myasthenic mice were rescued by sympathicomimetic treatment. In conclusion, this study identifies the neuromuscular junction as a target of the sympathetic nervous system and shows that sympathetic input is crucial for synapse maintenance and function.

Excessive erythrocytosis in adult mice overexpressing erythropoietin leads to hepatic, renal, neuronal, and muscular degeneration

2006 ◽  
Vol 291 (4) ◽  
pp. R947-R956 ◽  
Author(s):  
Katja Heinicke ◽  
Oliver Baum ◽  
Omolara O. Ogunshola ◽  
Johannes Vogel ◽  
Thomas Stallmach ◽  
...  
Keyword(s):  
Neuromuscular Junctions ◽  
Light And Electron Microscopy ◽  
Cardiovascular Complications ◽  
Multiple Organ ◽  
Independent Manner ◽  
Transgenic Mouse Line ◽  
Swim Performance ◽  
Adult Mice ◽  
Liver And Kidney ◽  
The Impact

To investigate the consequences of inborn excessive erythrocytosis, we made use of our transgenic mouse line (tg6) that constitutively overexpresses erythropoietin (Epo) in a hypoxia-independent manner, thereby reaching hematocrit levels of up to 0.89. We detected expression of human Epo in the brain and, to a lesser extent, in the lung but not in the heart, kidney, or liver of tg6 mice. Although no acute cardiovascular complications are observed, tg6 animals have a reduced lifespan. Decreased swim performance was observed in 5-mo-old tg6 mice. At about 7 mo, several tg6 animals developed spastic contractions of the hindlimbs followed by paralysis. Morphological analysis by light and electron microscopy showed degenerative processes in liver and kidney characterized by increased vascular permeability, chronic progressive inflammation, hemosiderin deposition, and general vasodilatation. Moreover, most of the animals showed severe nerve fiber degeneration of the sciatic nerve, decreased number of neuromuscular junctions, and degeneration of skeletal muscle fibers. Most probably, the developing demyelinating neuropathy resulted in muscular degeneration demonstrated in the extensor digitorum longus muscle. Taken together, chronically increased Epo levels inducing excessive erythrocytosis leads to multiple organ degeneration and reduced life expectancy. This model allows investigation of the impact of excessive erythrocytosis in individuals suffering from polycythemia vera, chronic mountain sickness, or in subjects tempted to abuse Epo by means of gene doping.

scholarly journals Skeletal Muscle in ALS: An Unappreciated Therapeutic Opportunity?

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 525
Author(s):  
Silvia Scaricamazza ◽  
Illari Salvatori ◽  
Alberto Ferri ◽  
Cristiana Valle
Keyword(s):  
Skeletal Muscle ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Skeletal Muscles ◽  
Neuromuscular Junctions ◽  
Neurodegenerative Disorder ◽  
Incurable Disease ◽  
Genetic Modifications ◽  
Therapeutic Opportunity ◽  
Metabolic Dysfunctions

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective degeneration of upper and lower motor neurons and by the progressive weakness and paralysis of voluntary muscles. Despite intense research efforts and numerous clinical trials, it is still an incurable disease. ALS had long been considered a pure motor neuron disease; however, recent studies have shown that motor neuron protection is not sufficient to prevent the course of the disease since the dismantlement of neuromuscular junctions occurs before motor neuron degeneration. Skeletal muscle alterations have been described in the early stages of the disease, and they seem to be mainly involved in the “dying back” phenomenon of motor neurons and metabolic dysfunctions. In recent years, skeletal muscles have been considered crucial not only for the etiology of ALS but also for its treatment. Here, we review clinical and preclinical studies that targeted skeletal muscles and discuss the different approaches, including pharmacological interventions, supplements or diets, genetic modifications, and training programs.

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.

scholarly journals The structure and function of ‘active zone material’ at synapses

2015 ◽  
Vol 370 (1672) ◽  
pp. 20140189 ◽  
Author(s):  
Joseph A. Szule ◽  
Jae Hoon Jung ◽  
Uel J. McMahan
Keyword(s):  
Spatial Resolution ◽  
Active Zone ◽  
Synaptic Vesicles ◽  
Neuromuscular Junctions ◽  
Electron Tomography ◽  
Structure And Function ◽  
Presynaptic Membrane ◽  
Axon Terminals ◽  
Active Zones ◽  
And Function

The docking of synaptic vesicles on the presynaptic membrane and their priming for fusion with it to mediate synaptic transmission of nerve impulses typically occur at structurally specialized regions on the membrane called active zones. Stable components of active zones include aggregates of macromolecules, ‘active zone material’ (AZM), attached to the presynaptic membrane, and aggregates of Ca 2+ -channels in the membrane, through which Ca 2+ enters the cytosol to trigger impulse-evoked vesicle fusion with the presynaptic membrane by interacting with Ca 2+ -sensors on the vesicles. This laboratory has used electron tomography to study, at macromolecular spatial resolution, the structure and function of AZM at the simply arranged active zones of axon terminals at frog neuromuscular junctions. The results support the conclusion that AZM directs the docking and priming of synaptic vesicles and essential positioning of Ca 2+ -channels relative to the vesicles' Ca 2+ -sensors. Here we review the findings and comment on their applicability to understanding mechanisms of docking, priming and Ca 2+ -triggering at other synapses, where the arrangement of active zone components differs.

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