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PloS One 2022Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons and skeletal muscle atrophy which is caused by ubiquitous deficiency...
Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by loss of motor neurons and skeletal muscle atrophy which is caused by ubiquitous deficiency in the survival motor neuron (SMN) protein. Several cellular defects contribute to sensory-motor circuit pathology in SMA mice, but the underlying mechanisms have often been studied in one mouse model without validation in other available models. Here, we used Smn2B/- mice to investigate specific behavioral, morphological, and functional aspects of SMA pathology that we previously characterized in the SMNΔ7 model. Smn2B/- SMA mice on a pure FVB/N background display deficits in body weight gain and muscle strength with onset in the second postnatal week and median survival of 19 days. Morphological analysis revealed severe loss of proprioceptive synapses on the soma of motor neurons and prominent denervation of neuromuscular junctions (NMJs) in axial but not distal muscles. In contrast, no evidence of cell death emerged from analysis of several distinct pools of lumbar motor neurons known to be lost in the disease. Moreover, SMA motor neurons from Smn2B/- mice showed robust nuclear accumulation of p53 but lack of phosphorylation of serine 18 at its amino-terminal, which selectively marks degenerating motor neurons in the SMNΔ7 mouse model. These results indicate that NMJ denervation and deafferentation, but not motor neuron death, are conserved features of SMA pathology in Smn2B/- mice.
Topics: Animals; Cell Death; Denervation; Disease Models, Animal; Mice; Mice, Inbred Strains; Motor Neurons; Muscular Atrophy, Spinal; Neurodegenerative Diseases; Survival of Motor Neuron 2 Protein
PubMed: 35913953
DOI: 10.1371/journal.pone.0267990 -
Stem Cell Research & Therapy Jul 2014Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor... (Review)
Review
Motor neurons are cells located in specific areas of the central nervous system, such as brain cortex (upper motor neurons), brain stem, and spinal cord (lower motor neurons), which maintain control over voluntary actions. Motor neurons are affected primarily by a wide spectrum of neurological disorders, generally indicated as motor neuron diseases (MNDs): these disorders share symptoms related to muscular atrophy and paralysis leading to death. No effective treatments are currently available. Stem cell-derived motor neurons represent a promising research tool in disease modeling, drug screening, and development of therapeutic approaches for MNDs and spinal cord injuries. Directed differentiation of human pluripotent stem cells - human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) - toward specific lineages is the first crucial step in order to extensively employ these cells in early human development investigation and potential clinical applications. Induced pluripotent stem cells (iPSCs) can be generated from patients' own somatic cells (for example, fibroblasts) by reprogramming them with specific factors. They can be considered embryonic stem cell-like cells, which express stem cell markers and have the ability to give rise to all three germ layers, bypassing the ethical concerns. Thus, hiPSCs constitute an appealing alternative source of motor neurons. These motor neurons might be a great research tool, creating a model for investigating the cellular and molecular interactions underlying early human brain development and pathologies during neurodegeneration. Patient-specific iPSCs may also provide the premises for autologous cell replacement therapies without related risks of immune rejection. Here, we review the most recent reported methods by which hESCs or iPSCs can be differentiated toward functional motor neurons with an overview on the potential clinical applications.
Topics: Biomarkers; Cell Culture Techniques; Cell Differentiation; Embryonic Stem Cells; Humans; Induced Pluripotent Stem Cells; Motor Neurons
PubMed: 25157556
DOI: 10.1186/scrt476 -
Neurotherapeutics : the Journal of the... Apr 2015Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a clinically heterogeneous disorder characterized by loss of motor neurons, resulting in paralysis and death. Multiple mechanisms of motor neuron injury have been implicated based upon the more than 20 different genetic causes of familial ALS. These inherited mutations compromise diverse motor neuron pathways leading to cell-autonomous injury. In the ALS transgenic mouse models, however, motor neurons do not die alone. Cell death is noncell-autonomous dependent upon a well orchestrated dialogue between motor neurons and surrounding glia and adaptive immune cells. The pathogenesis of ALS consists of 2 stages: an early neuroprotective stage and a later neurotoxic stage. During early phases of disease progression, the immune system is protective with glia and T cells, especially M2 macrophages/microglia, and T helper 2 cells and regulatory T cells, providing anti-inflammatory factors that sustain motor neuron viability. As the disease progresses and motor neuron injury accelerates, a second rapidly progressing phase develops, characterized by M1 macrophages/microglia, and proinflammatory T cells. In rapidly progressing ALS patients, as in transgenic mice, neuroprotective regulatory T cells are significantly decreased and neurotoxicity predominates. Our own therapeutic efforts are focused on modulating these neuroinflammatory pathways. This review will focus on the cellular players involved in neuroinflammation in ALS and current therapeutic strategies to enhance neuroprotection and suppress neurotoxicity with the goal of arresting the progressive and devastating nature of ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Anti-Inflammatory Agents; Cytokines; Disease Models, Animal; Humans; Inflammation; Mice; Motor Neurons; Neuroglia
PubMed: 25567201
DOI: 10.1007/s13311-014-0329-3 -
Developmental Dynamics : An Official... Apr 2018Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key... (Review)
Review
Motor behaviors are precisely controlled by the integration of sensory and motor systems in the central nervous system (CNS). Proprioceptive sensory neurons, key components of the sensory system, are located in the dorsal root ganglia and project axons both centrally to the spinal cord and peripherally to muscles and tendons, communicating peripheral information about the body to the CNS. Changes in muscle length detected by muscle spindles, and tension variations in tendons conveyed by Golgi tendon organs, are communicated to the CNS through group Ia /II, and Ib proprioceptive sensory afferents, respectively. Group Ib proprioceptive sensory neurons connect with motor neurons indirectly through spinal interneurons, whereas group Ia/II axons form both direct (monosynaptic) and indirect connections with motor neurons. Although monosynaptic sensory-motor circuits between spindle proprioceptive sensory neurons and motor neurons have been extensively studied since 1950s, the molecular mechanisms underlying their formation and upkeep have only recently begun to be understood. We will discuss our current understanding of the molecular foundation of monosynaptic circuit development and maintenance involving proprioceptive sensory neurons and motor neurons in the mammalian spinal cord. Developmental Dynamics 247:581-587, 2018. © 2017 Wiley Periodicals, Inc.
Topics: Animals; Central Nervous System; Humans; Motor Neurons; Proprioception; Sensory Receptor Cells; Spinal Cord
PubMed: 29226492
DOI: 10.1002/dvdy.24611 -
Philosophical Transactions of the Royal... Sep 2018The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm.... (Review)
Review
The intrinsic oscillatory activity of central pattern generators underlies motor rhythm. We review and discuss recent findings that address the origin of motor rhythm. These studies propose that the A- and mid-body B-class excitatory motor neurons at the ventral cord function as non-bursting intrinsic oscillators to underlie body undulation during reversal and forward movements, respectively. Proprioception entrains their intrinsic activities, allows phase-coupling between members of the same class motor neurons, and thereby facilitates directional propagation of undulations. Distinct pools of premotor interneurons project along the ventral nerve cord to innervate all members of the A- and B-class motor neurons, modulating their oscillations, as well as promoting their bi-directional coupling. The two motor sub-circuits, which consist of oscillators and descending inputs with distinct properties, form the structural base of dynamic rhythmicity and flexible partition of the forward and backward motor states. These results contribute to a continuous effort to establish a mechanistic and dynamic model of the sensorimotor system. exhibits rich sensorimotor functions despite a small neuron number. These findings implicate a circuit-level functional compression. By integrating the role of rhythm generation and proprioception into motor neurons, and the role of descending regulation of oscillators into premotor interneurons, this numerically simple nervous system can achieve a circuit infrastructure analogous to that of anatomically complex systems. has manifested itself as a compact model to search for general principles of sensorimotor behaviours.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling at cellular resolution'.
Topics: Animals; Caenorhabditis elegans; Interneurons; Locomotion; Motor Neurons; Periodicity
PubMed: 30201835
DOI: 10.1098/rstb.2017.0370 -
Journal of Biosciences 2022Spinal cord injury (SCI) is one of the most devastating injuries which causes either complete or partial loss of movement, balance, muscular coordination and endurance....
Spinal cord injury (SCI) is one of the most devastating injuries which causes either complete or partial loss of movement, balance, muscular coordination and endurance. Electromagnetic field (EMF) stimulation has been shown to reduce muscle atrophy and fiber-type switching and improves muscle function in a hindlimb suspension model. The present study aims to elucidate the therapeutic potential of EMF stimulation on motor neuron excitability, soleus muscle morphology and function in complete SCI rats. Thirty-six adult male Wistar rats were randomly divided into Sham, SCI and SCI+EMF groups. Complete transection was done at the T13 spinal level, followed by whole-body EMF exposure for 7 or 14 days. Hyper-reflexia, muscle atrophy, reduction in twitch and tetanic force with earlier onset of fatigue was evident in the SCI group. EMF stimulation showed significant improvement in H and M wave parameters, H/M ratio, muscle twitch and tetanic force, fusion frequency and fatigability. A significant increase in regenerating myofibers and reduction in muscle degeneration following EMF was evident on histopathological examination. Further, EMF significantly increased myogenic protein levels responsible for muscle regeneration. Our study demonstrates for the first time the potential of EMF to modulate motor neuron excitability and muscle contractile function in SCI rats through activity-dependent mechanisms.
Topics: Rats; Male; Animals; Electromagnetic Fields; Rats, Wistar; Motor Neurons; Muscle, Skeletal; Muscular Atrophy; Spinal Cord Injuries
PubMed: 36510440
DOI: No ID Found -
Cellular and Molecular Life Sciences :... Jun 2019The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear... (Review)
Review
The nuclear pore is the gatekeeper of nucleocytoplasmic transport and signaling through which a vast flux of information is continuously exchanged between the nuclear and cytoplasmic compartments to maintain cellular homeostasis. A unifying and organizing principle has recently emerged that cements the notion that several forms of amyotrophic lateral sclerosis (ALS), and growing number of other neurodegenerative diseases, co-opt the dysregulation of nucleocytoplasmic transport and that this impairment is a pathogenic driver of neurodegeneration. The understanding of shared pathomechanisms that underpin neurodegenerative diseases with impairments in nucleocytoplasmic transport and how these interface with current concepts of nucleocytoplasmic transport is bound to illuminate this fundamental biological process in a yet more physiological context. Here, I summarize unresolved questions and evidence and extend basic and critical concepts and challenges of nucleocytoplasmic transport and its role in the pathogenesis of neurodegenerative diseases, such as ALS. These principles will help to appreciate the roles of nucleocytoplasmic transport in the pathogenesis of ALS and other neurodegenerative diseases, and generate a framework for new ideas of the susceptibility of motoneurons, and possibly other neurons, to degeneration by dysregulation of nucleocytoplasmic transport.
Topics: Active Transport, Cell Nucleus; Amyotrophic Lateral Sclerosis; Animals; Cell Nucleus; Cytoplasm; Humans; Motor Neuron Disease; Motor Neurons; Neurodegenerative Diseases
PubMed: 30742233
DOI: 10.1007/s00018-019-03029-0 -
Biomolecules Dec 2021The vertebrate neuromuscular junction (NMJ) is formed by a presynaptic motor nerve terminal and a postsynaptic muscle specialization. Cumulative evidence reveals that...
The vertebrate neuromuscular junction (NMJ) is formed by a presynaptic motor nerve terminal and a postsynaptic muscle specialization. Cumulative evidence reveals that Wnt ligands secreted by the nerve terminal control crucial steps of NMJ synaptogenesis. For instance, the Wnt3 ligand is expressed by motor neurons at the time of NMJ formation and induces postsynaptic differentiation in recently formed muscle fibers. However, the behavior of presynaptic-derived Wnt ligands at the vertebrate NMJ has not been deeply analyzed. Here, we conducted overexpression experiments to study the expression, distribution, secretion, and function of Wnt3 by transfection of the motor neuron-like NSC-34 cell line and by in ovo electroporation of chick motor neurons. Our findings reveal that Wnt3 is transported along motor axons in vivo following a vesicular-like pattern and reaches the NMJ area. In vitro, we found that endogenous Wnt3 expression increases as the differentiation of NSC-34 cells proceeds. Although NSC-34 cells overexpressing Wnt3 do not modify their morphological differentiation towards a neuronal phenotype, they effectively induce acetylcholine receptor clustering on co-cultured myotubes. These findings support the notion that presynaptic Wnt3 is transported and secreted by motor neurons to induce postsynaptic differentiation in nascent NMJs.
Topics: Animals; Cell Differentiation; Cell Line; Chick Embryo; Coculture Techniques; Electroporation; Ligands; Mice; Motor Neurons; Neuromuscular Junction; Receptors, Cholinergic; Wnt3 Protein
PubMed: 34944540
DOI: 10.3390/biom11121898 -
Experimental Neurology Dec 2021Cervical spinal cord injury (cSCI) severs bulbospinal projections to respiratory motor neurons, paralyzing respiratory muscles below the injury. C2 spinal hemisection...
Cervical spinal cord injury (cSCI) severs bulbospinal projections to respiratory motor neurons, paralyzing respiratory muscles below the injury. C2 spinal hemisection (C2Hx) is a model of cSCI often used to study spontaneous and induced plasticity and breathing recovery post-injury. One key assumption is that C2Hx dennervates motor neurons below the injury, but does not affect their survival. However, a recent study reported substantial bilateral motor neuron death caudal to C2Hx. Since phrenic motor neuron (PMN) death following C2Hx would have profound implications for therapeutic strategies designed to target spared neural circuits, we tested the hypothesis that C2Hx minimally impacts PMN survival. Using improved retrograde tracing methods, we observed no loss of PMNs at 2- or 8-weeks post-C2Hx. We also observed no injury-related differences in ChAT or NeuN immunolabeling within labelled PMNs. Although we found no evidence of PMN loss following C2Hx, we cannot rule out neuronal loss in other motor pools. These findings address an essential prerequisite for studies that utilize C2Hx as a model to explore strategies for inducing plasticity and/or regeneration within the phrenic motor system, as they provide important insights into the viability of phrenic motor neurons as therapeutic targets after high cervical injury.
Topics: Animals; Cell Survival; Cervical Cord; Male; Motor Neurons; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Spinal Cord Injuries
PubMed: 34363808
DOI: 10.1016/j.expneurol.2021.113832 -
The Journal of Physiology Apr 2018Although adenosine 2A (A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing...
KEY POINTS
Although adenosine 2A (A ) receptor activation triggers specific cell signalling cascades, the ensuing physiological outcomes depend on the specific cell type expressing these receptors. Cervical spinal adenosine 2A (A ) receptor activation elicits a prolonged facilitation in phrenic nerve activity, which was nearly abolished following intrapleural A receptor siRNA injections. A receptor siRNA injections selectively knocked down A receptors in cholera toxin B-subunit-identified phrenic motor neurons, sparing cervical non-phrenic motor neurons. Collectively, our results support the hypothesis that phrenic motor neurons express the A receptors relevant to A receptor-induced phrenic motor facilitation. Upregulation of A receptor expression in the phrenic motor neurons per se may potentially be a useful approach to increase phrenic motor neuron excitability in conditions such as spinal cord injury.
ABSTRACT
Cervical spinal adenosine 2A (A ) receptor activation elicits a prolonged increase in phrenic nerve activity, an effect known as phrenic motor facilitation (pMF). The specific cervical spinal cells expressing the relevant A receptors for pMF are unknown. This is an important question since the physiological outcome of A receptor activation is highly cell type specific. Thus, we tested the hypothesis that the relevant A receptors for pMF are expressed in phrenic motor neurons per se versus non-phrenic neurons of the cervical spinal cord. A receptor immunostaining significantly colocalized with NeuN-positive neurons (89 ± 2%). Intrapleural siRNA injections were used to selectively knock down A receptors in cholera toxin B-subunit-labelled phrenic motor neurons. A receptor knock-down was verified by a ∼45% decrease in A receptor immunoreactivity within phrenic motor neurons versus non-targeting siRNAs (siNT; P < 0.05). There was no evidence for knock-down in cervical non-phrenic motor neurons. In rats that were anaesthetized, subjected to neuromuscular blockade and ventilated, pMF induced by cervical (C3-4) intrathecal injections of the A receptor agonist CGS21680 was greatly attenuated in siA (21%) versus siNT treated rats (147%; P < 0.01). There were no significant effects of siA on phrenic burst frequency. Collectively, our results support the hypothesis that phrenic motor neurons express the A receptors relevant to A receptor-induced pMF.
Topics: Action Potentials; Adenosine A2 Receptor Agonists; Animals; Cholera Toxin; Male; Motor Neurons; Phrenic Nerve; Rats; Rats, Sprague-Dawley; Receptor, Adenosine A2A
PubMed: 29388230
DOI: 10.1113/JP275462