scholarly journals Contingent intramuscular boosting of P2XR7 axis improves motor function in transgenic ALS mice

2021 ◽  
Vol 79 (1) ◽  
Author(s):  
Paola Fabbrizio ◽  
Jessica D’Agostino ◽  
Cassandra Margotta ◽  
Giulia Mella ◽  
Nicolò Panini ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Target Tissue ◽  
Neuron Death ◽  
Supporting Cells ◽  
Progressive Degeneration ◽  
Motor Neuron Death ◽  
The Central Nervous System

AbstractAmyotrophic lateral sclerosis is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons and severe muscle atrophy without effective treatment. Most research on the disease has been focused on studying motor neurons and supporting cells of the central nervous system. Strikingly, the recent observations have suggested that morpho-functional alterations in skeletal muscle precede motor neuron degeneration, bolstering the interest in studying muscle tissue as a potential target for the delivery of therapies. We previously showed that the systemic administration of the P2XR7 agonist, 2′(3′)-O‐(4-benzoylbenzoyl) adenosine 5-triphosphate (BzATP), enhanced the metabolism and promoted the myogenesis of new fibres in the skeletal muscles of SOD1G93A mice. Here we further corroborated this evidence showing that intramuscular administration of BzATP improved the motor performance of ALS mice by enhancing satellite cells and the muscle pro-regenerative activity of infiltrating macrophages. The preservation of the skeletal muscle retrogradely propagated along with the motor unit, suggesting that backward signalling from the muscle could impinge on motor neuron death. In addition to providing the basis for a suitable adjunct multisystem therapeutic approach in ALS, these data point out that the muscle should be at the centre of ALS research as a target tissue to address novel therapies in combination with those oriented to the CNS.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

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 Locomotor deficits in ALS mice are paralleled by loss of V1-interneuron-connections onto fast motor neurons

2020 ◽  
Author(s):  
Ilary Allodi ◽  
Roser Montañana-Rosell ◽  
Raghavendra Selvan ◽  
Peter Löw ◽  
Ole Kiehn
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Inhibitory Synapses ◽  
Neuron Death ◽  
Spinal Interneurons ◽  
Pathway Interaction ◽  
Fast Twitch Muscle ◽  
Motor Neuron Death ◽  
Locomotor Deficits ◽  
Induced Changes

AbstractALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle fibers exhibit preferential degeneration. The reason for differential vulnerability of fast motor neurons, and its consequence on motor output is not known. Here, we show that fast motor neurons receive more inhibitory synaptic inputs than slow motor neurons, and loss of inhibitory synapses onto fast motor neurons precedes disease progression in the SOD1G93A mouse model of ALS. Loss of inhibitory synapses on fast motor neurons is accounted for by a loss of synapses from inhibitory V1 spinal interneurons. Deficits in V1-motor neuron connectivity appear prior to motor neuron death and are paralleled by development of specific SOD1G93A locomotor deficits. These distinct SOD1G93A locomotor deficits are phenocopied by silencing of inhibitory V1 spinal interneurons in wild-type mice. Silencing inhibitory V1 spinal interneurons does not exacerbate SOD1G93A locomotor deficits, suggesting phenotypic pathway interaction. Our study identifies a potential cell non-autonomous source of motor neuronal vulnerability in ALS, and links ALS-induced changes in locomotor phenotypes to inhibitory V1 interneurons.

scholarly journals Transcriptomic Analysis of MAPK Signaling in NSC-34 Motor Neurons Treated with Vitamin E

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1081 ◽  
Author(s):  
Luigi Chiricosta ◽  
Agnese Gugliandolo ◽  
Giuseppe Tardiolo ◽  
Placido Bramanti ◽  
Emanuela Mazzon
Keyword(s):  
Vitamin E ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Mapk Signaling ◽  
Fold Change ◽  
Neuron Death ◽  
Log2 Fold Change ◽  
Motor Neuron Death ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Vitamin E family is composed of different tocopherols and tocotrienols that are well-known as antioxidants but that exert also non-antioxidant effects. Oxidative stress may be involved in the progression of neurodegenerative disorders including amyotrophic lateral sclerosis (ALS), characterized by motor neuron death. The aim of the study was the evaluation of the changes induced in the transcriptional profile of NSC-34 motor neurons treated with α-tocopherol. In particular, cells were treated for 24 h with 10 µM α-tocopherol, RNA was extracted and transcriptomic analysis was performed using Next Generation Sequencing. Vitamin E treatment modulated MAPK signaling pathway. The evaluation revealed that 34 and 12 genes, respectively belonging to “Classical MAP kinase pathway” and “JNK and p38 MAP kinase pathway”, were involved. In particular, a downregulation of the genes encoding for p38 (Log2 fold change −0.87 and −0.67) and JNK (Log2 fold change −0.16) was found. On the contrary, the gene encoding for ERK showed a higher expression in cells treated with vitamin E (Log2 fold change 0.30). Since p38 and JNK seem more involved in cell death, while ERK in cell survival, the data suggested that vitamin E treatment may exert a protective role in NSC-34 motor neurons. Moreover, Vitamin E treatment reduced the expression of the genes which encode proteins involved in mitophagy. These results indicate that vitamin E may be an efficacious therapy in preventing motor neuron death, opening new strategies for those diseases that involve motor neurons, including ALS.

scholarly journals A review: Management of motor neuron diseases

2022 ◽  
Vol 7 (4) ◽  
pp. 292-294
Author(s):  
Aarti Chopra ◽  
Ravi Kumar ◽  
Girendra Kumar Gautam
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Age At Onset ◽  
Motor Neuron Diseases ◽  
Progressive Degeneration ◽  
Review Management ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Motor neuron diseases are a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. These might affect the upper motor neurons, lower motor neurons, or both. The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. Amyotrophic lateral sclerosis (ALS) has been documented to be fatal within three years of onset. This activity focuses on amyotrophic lateral sclerosis as the prototype of MND, which affects both the upper and the lower motor neurons and discusses the role of inter-professional team in the differential diagnosis, evaluation, treatment, and prognostication. It also discusses various other phenotypes of MND with an emphasis on their distinguishing features in requisite detail.

scholarly journals MyomiRNAs Dysregulation in ALS Rehabilitation

2019 ◽  
Vol 9 (1) ◽  
pp. 8 ◽  
Author(s):  
Valentina Pegoraro ◽  
Antonio Merico ◽  
Corrado Angelini
Keyword(s):  
Skeletal Muscle ◽  
Motor Neuron ◽  
Aerobic Exercise ◽  
Muscle Atrophy ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Specific Effect ◽  
Cell Types ◽  
Molecular Data

Amyotrophic lateral sclerosis (ALS) is a rare, progressive, neurodegenerative disorder caused by degeneration of upper and lower motor neurons. The disease process leads, because of lower motor neuron involvement, to progressive muscle atrophy, weakness, and fasciculations and for the upper motor neuron involvement leads to spasticity. Muscle atrophy in ALS is caused by a neural dysregulation in the molecular network controlling fast and slow muscle fibers. 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 are involved in different 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 contribute to 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. This is a preliminary study, in which we correlated clinical scales with molecular data on myomiRs. After six weeks of moderate aerobic exercise, we found lower levels in serum of myomiRNAs. Our data suggest that circulating miRNAs changed during skeletal muscle recovery in response to physical rehabilitation in ALS. However, no firm conclusions can be made on the ALS-specific effect of exercise on miRNA levels.

scholarly journals Ligand-independent activation of the P2X7 receptor by Hsp90 inhibition stimulates motor neuron apoptosis

2019 ◽  
Vol 244 (11) ◽  
pp. 901-914
Author(s):  
Amy L Strayer ◽  
Cassandra N Dennys-Rivers ◽  
Karina C Ricart ◽  
Narae Bae ◽  
Joseph S Beckman ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
P2x7 Receptor ◽  
Receptor Activation ◽  
Neuron Death ◽  
Hsp90 Inhibition ◽  
Highly Sensitive ◽  
Motor Neuron Death ◽  
Lateral Sclerosis ◽  
Neuron Apoptosis

Activation of the extracellular ATP ionotropic receptor P2X7 stimulates motor neuron apoptosis, whereas its inhibition in cell and animal models of amyotrophic lateral sclerosis can be protective. These observations suggest that P2X7 receptor activation is relevant to motor neuron disease and that it could be targeted for therapeutic development. Heat shock protein 90 (Hsp90) is an integral regulatory component of the P2X7 receptor complex, antagonizing ligand-induced receptor activation. Here, we show that the repressive activity of Hsp90 on P2X7 receptor activation in primary motor neurons is highly sensitive to inhibition. Primary motor neurons in culture are 100-fold more sensitive to Hsp90 inhibition by geldanamycin than other neuronal populations. Pharmacological inhibition and down-regulation of the P2X7 receptor prevented motor neuron apoptosis triggered by Hsp90 inhibition, which occurred in the absence of extracellular ATP. These observations suggest that inhibition of a seemingly motor neuron specific pool of Hsp90 leads to ligand independent activation of P2X7 receptor and motor neuron death. Downstream of Hsp90 inhibition, P2X7 receptor activated the phosphatase and tensin homolog (TPEN), which in turn suppressed the pro-survival phosphatidyl inositol 3 kinase (PI3K)/Akt pathway, leading to Fas-dependent motor neuron apoptosis. Conditions altering the interaction between P2X7 receptor and Hsp90, such as recruitment of Hsp90 to other subcellular compartments under stress conditions, or nitration following oxidative stress can induce motor neuron death. These findings may have broad implications in neurodegenerative disorders, including amyotrophic lateral sclerosis, in which activation of P2X7 receptor may be involved in both autonomous and non-autonomous motor neurons death. Impact statement Here we show that a motor neuron specific pool of Hsp90 that is highly sensitive to geldanamycin inhibition represses ligand-independent activation of P2X7 receptor and is critical to motor neuron survival. Activation of P2X7 receptor by Hsp90 inhibition triggers motor neuron apoptosis through the activation of PTEN, which in turn inhibits the PI3 kinase/Akt survival pathway. Thus, inhibition of Hsp90 for therapeutic applications may have the unexpected negative consequence of decreasing the activity of trophic pathways in motor neurons. The inhibition of Hsp90 as a therapeutic approach may require the identification of the Hsp90 complexes involved in pathogenic processes and the development of inhibitors selective for these complexes.

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.

Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model

2008 ◽  
Vol 32 (2) ◽  
pp. 207-218 ◽  
Author(s):  
Jose-Luis Gonzalez de Aguilar ◽  
Christa Niederhauser-Wiederkehr ◽  
Benoît Halter ◽  
Marc De Tapia ◽  
Franck Di Scala ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neuron ◽  
Gene Profiling ◽  
Specific Gene ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Gene Regulations ◽  
Lateral Sclerosis

Muscle atrophy is a major hallmark of amyotrophic lateral sclerosis (ALS), the most frequent adult-onset motor neuron disease. To define the full set of alterations in gene expression in skeletal muscle during the course of the disease, we used the G86R superoxide dismutase-1 transgenic mouse model of ALS and performed high-density oligonucleotide microarrays. We compared these data to those obtained by axotomy-induced denervation. A major set of gene regulations in G86R muscles resembled those of surgically denervated muscles, but many others appeared specific to the ALS condition. The first significant transcriptional changes appeared in a subpopulation of mice before the onset of overt clinical symptoms and motor neuron death. These early changes affected genes involved in detoxification (e.g., ALDH3, metallothionein-2, and thioredoxin-1) and regeneration (e.g., BTG1, RB1, and RUNX1) but also tissue degradation (e.g., C/EBPδ and DDIT4) and cell death (e.g., ankyrin repeat domain-1, CDKN1A, GADD45α, and PEG3). Of particular interest, metallothionein-1 and -2, ATF3, cathepsin-Z, and galectin-3 genes appeared, among others, commonly regulated in both skeletal muscle (our present data) and spinal motor neurons (as previously reported) of paralyzed ALS mice. The importance of these findings is twofold. First, they designate the distal part of the motor unit as a primary site of disease. Second, they identify specific gene regulations to be explored in the search for therapeutic strategies that could alleviate disease before motor neuron death manifests clinically.

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