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 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.

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 The Amyloid Precursor-like Protein APL-1 Regulates Axon Regeneration

2018 ◽  
Author(s):  
Lewie Zeng ◽  
Rachid El Bejjani ◽  
Marc Hammarlund
Keyword(s):  
Motor Neurons ◽  
Neuronal Development ◽  
Axon Regeneration ◽  
Neuronal Response ◽  
Small Gtpase ◽  
C Elegans ◽  
Protein Levels ◽  
Mature Neurons ◽  
And Function

AbstractMembers of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use the C. elegans GABAergic motor neurons to study the post-developmental function of the APP-like protein APL-1 in vivo. We find that apl-1 has minimum roles in the maintenance of gross neuron morphology and function. However, we show that apl-1 is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to 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 Short-term enhancement of motor neuron synaptic exocytosis during early aging extends lifespan in Caenorhabditis elegans

2020 ◽  
Vol 245 (17) ◽  
pp. 1552-1559
Author(s):  
Tsui-Ting Ching ◽  
Yen-Chieh Chen ◽  
Guang Li ◽  
Jianfeng Liu ◽  
X Z Shawn Xu ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Early Stage ◽  
Functional Decline ◽  
The Elderly ◽  
Term Treatment ◽  
Short Term ◽  
Short Term Treatment ◽  
C Elegans ◽  
Synaptic Exocytosis

Age-related mobility decline is often associated with negative physical and psychological outcomes, such as frailty, in the elderly population. In C. elegans, during the early stage of the aging process, a progressive deficit of synaptic exocytosis in the motor neurons results in a functional decline at the neuromuscular junctions, which eventually leads to degeneration of both neurons and muscles. This age-dependent functional decline can be ameliorated by pharmacological interventions, such as arecoline, a muscarinic AChR agonist known to promote synaptic exocytosis at the neuromuscular junctions. In this study, we found that a short-term treatment of arecoline during the early stage of aging, when the NMJ functional decline begins, not only slows muscle tissue aging, but also extends lifespan in C. elegans. We have also demonstrated that arecoline acts on the GAR-2/PLCβ pathway in the motor neurons to increases longevity. Together, our findings suggest that synaptic transmission in aging motor neurons may serve as a potential target for pharmacological interventions to promote both health span and lifespan, when applied at the early stage aging. Impact statement The functional decline of motor activity is a common feature in almost all aging animals that leads to frailty, loss of independence, injury, and even death in the elderly population. Thus, understanding the molecular mechanism that drives the initial stage of this functional decline and developing strategies to increase human healthspan and even lifespan by targeting this process would be of great interests to the field. In this study, we found that by precisely targeting the motor neurons to potentiate its synaptic releases either genetically or pharmacologically, we can not only delay the functional aging at NMJs but also slow the rate of aging at the organismal level. Most importantly, we have demonstrated that a critical window of time, that is the early stage of NMJs functional decline, is required for the beneficial effects. A short-term treatment within this time period is sufficient to extend the animals’ lifespan.

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.

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