scholarly journals Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ilary Allodi ◽  
Roser Montañana-Rosell ◽  
Raghavendra Selvan ◽  
Peter Löw ◽  
Ole Kiehn
Keyword(s):  
Mouse Model ◽  
Motor Neurons ◽  
Inhibitory Synapses ◽  
Neuron Death ◽  
Spinal Interneurons ◽  
Fast Twitch Muscle ◽  
Motor Neuron Death ◽  
Locomotor Deficits ◽  
Induced Changes ◽  
Fast Twitch

AbstractALS is characterized by progressive inability to execute movements. Motor neurons innervating fast-twitch muscle-fibers preferentially degenerate. The reason for this differential vulnerability and its consequences on motor output is not known. Here, we uncover that fast motor neurons receive stronger inhibitory synaptic inputs than slow motor neurons, and disease progression in the SOD1G93A mouse model leads to specific loss of inhibitory synapses onto fast motor neurons. Inhibitory V1 interneurons show similar innervation pattern and loss of synapses. Moreover, from postnatal day 63, there is a loss of V1 interneurons in the SOD1G93A mouse. The V1 interneuron degeneration appears before motor neuron death and is paralleled by the development of a specific locomotor deficit affecting speed and limb coordination. This distinct ALS-induced locomotor deficit is phenocopied in wild-type mice but not in SOD1G93A mice after appearing of the locomotor phenotype when V1 spinal interneurons are silenced. Our study identifies a potential source of non-autonomous motor neuronal vulnerability in ALS and links ALS-induced changes in locomotor phenotype to inhibitory V1-interneurons.

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 Calpain-Dependent Degradation of Nucleoporins Contributes to Motor Neuron Death in a Mouse Model of Chronic Excitotoxicity

2017 ◽  
Vol 37 (36) ◽  
pp. 8830-8844 ◽  
Author(s):  
Kaori Sugiyama ◽  
Tomomi Aida ◽  
Masatoshi Nomura ◽  
Ryoichi Takayanagi ◽  
Hanns U. Zeilhofer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Motor Neuron ◽  
Neuron Death ◽  
Motor Neuron Death

scholarly journals The primary locus of motor neuron death in an ALS–PDC mouse model

Neuroreport ◽  
2009 ◽  
Vol 20 (14) ◽  
pp. 1284-1289 ◽  
Author(s):  
Grace Lee ◽  
Tony Chu ◽  
Christopher A. Shaw
Keyword(s):  
Mouse Model ◽  
Motor Neuron ◽  
Neuron Death ◽  
Motor Neuron Death

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 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 Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

2019 ◽  
Author(s):  
Christian Simon ◽  
Meaghan Van Alstyne ◽  
Francesco Lotti ◽  
Elena Bianchetti ◽  
Sarah Tisdale ◽  
...  
Keyword(s):  
Mouse Model ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Muscular Atrophy ◽  
Neuron Death ◽  
Motor Neuron Death

scholarly journals Edaravone May Prevent Ferroptosis in ALS

2020 ◽  
Vol 21 (8) ◽  
pp. 776-780 ◽  
Author(s):  
Snežana Spasić ◽  
Aleksandra Nikolić-Kokić ◽  
Srđan Miletić ◽  
Zorana Oreščanin-Dušić ◽  
Mihajlo B. Spasić ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Disease Onset ◽  
Cell Types ◽  
Therapeutic Approaches ◽  
Neuron Death ◽  
Motor Neuron Death ◽  
Multiple Cell ◽  
New Treatment ◽  
Lateral Sclerosis

Radicava™ (Edaravone) was approved the Food and Drug Administration (FDA) as a new treatment for amyotrophic lateral sclerosis (ALS). Edaravone is a synthetic antioxidant that specifically targets oxidative damage interacting with lipid radicals in the cell. In ALS disease the multiple cell types are involved in devastating loss of motor neurons. Mutations and biochemical changes in various cell types jointly contribute to motor neuron death, disease onset, and disease progression. The overall mechanism of neurodegeneration in ALS is still not completely understood. Dying motor neurons have been reported to exhibit features of apoptosis. However, non-apoptotic features of dying motor neurons have also been reported such as ferroptosis. The role of Edaravone in the prevention of ferroptosis in parallel with other therapeutic approaches to ALS therapy is discussed.

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.

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