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Current Opinion in Neurobiology Dec 2018The embryonic generation of motor neurons is a complex process involving progenitor patterning, fate specification, differentiation, and maturation. Throughout this... (Review)
Review
The embryonic generation of motor neurons is a complex process involving progenitor patterning, fate specification, differentiation, and maturation. Throughout this progression, the differential expression of transcription factors has served as our road map for the eventual cell fate of nascent motor neurons. Recent findings from in vivo and in vitro models of motor neuron development have expanded our understanding of how transcription factors govern motor neuron identity and their individual regulatory mechanisms. With the advent of next generation sequencing approaches, researchers now have unprecedented access to the gene regulatory dynamics involved in motor neuron development and are uncovering new connections linking neurodevelopment and neurodegenerative disease.
Topics: Animals; Cell Differentiation; Gene Expression Regulation, Developmental; Motor Neurons; Transcription Factors
PubMed: 29694927
DOI: 10.1016/j.conb.2018.04.012 -
Neurotherapeutics : the Journal of the... Jul 2022
Topics: Humans; Motor Neuron Disease; Motor Neurons
PubMed: 36171516
DOI: 10.1007/s13311-022-01307-7 -
International Journal of Molecular... May 2021Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense... (Review)
Review
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Humans; Motor Neurons; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Phenotype; Survival of Motor Neuron 1 Protein
PubMed: 34072857
DOI: 10.3390/ijms22115913 -
Cells Jun 2023Motor Neuron Diseases (MND) are neurological disorders characterized by a loss of varying motor neurons resulting in decreased physical capabilities. Current research is... (Review)
Review
Motor Neuron Diseases (MND) are neurological disorders characterized by a loss of varying motor neurons resulting in decreased physical capabilities. Current research is focused on hindering disease progression by determining causes of motor neuron death. Metabolic malfunction has been proposed as a promising topic when targeting motor neuron loss. Alterations in metabolism have also been noted at the neuromuscular junction (NMJ) and skeletal muscle tissue, emphasizing the importance of a cohesive system. Finding metabolism changes consistent throughout both neurons and skeletal muscle tissue could pose as a target for therapeutic intervention. This review will focus on metabolic deficits reported in MNDs and propose potential therapeutic targets for future intervention.
Topics: Humans; Motor Neuron Disease; Motor Neurons; Neuromuscular Junction; Muscle, Skeletal; Nerve Degeneration
PubMed: 37296656
DOI: 10.3390/cells12111536 -
Revue Neurologique Mar 2022Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can... (Review)
Review
Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category 'probable' PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.
Topics: Amyotrophic Lateral Sclerosis; Consensus; Humans; Motor Neuron Disease; Motor Neurons
PubMed: 34243936
DOI: 10.1016/j.neurol.2021.04.008 -
Cellular and Molecular Life Sciences :... Jun 2021Neuromuscular system is constituted of multi-fibrillar muscles, tendons, motor neurons and associated muscle stem cells. Stereotyped pattern of muscle innervation and... (Review)
Review
Neuromuscular system is constituted of multi-fibrillar muscles, tendons, motor neurons and associated muscle stem cells. Stereotyped pattern of muscle innervation and muscle-specific interactions with tendon cells suggest that neuromuscular system develops in a coordinated way. Remarkably, upon regeneration, coordinated assembly of all neuromuscular components is also critical to rebuild functional muscle. Thus, to ensure muscle function, the neuromuscular system components need to interact both during development and regeneration. Over the last decades, interactions between muscles and tendons, muscles and motor neurons and between muscles and muscle stem cells have been extensively analysed and documented. However, only recent evidence indicates that muscle stem cells interact with motor neurons and that these interactions contribute to building functional muscle both during development and regeneration. From this perspective, we discuss here the relationship between muscle stem cells and motor neurons during Drosophila neuromuscular system development and adverse impact of affected muscle stem cell-motor neuron interactions in regenerating vertebrate muscle.
Topics: Animals; Humans; Motor Neurons; Muscles; Neuromuscular Junction; Regeneration; Stem Cells
PubMed: 33861361
DOI: 10.1007/s00018-021-03838-2 -
Neural Plasticity 2017Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years,... (Review)
Review
Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis.
Topics: Brain; Child; Humans; Motor Neuron Disease; Motor Neurons; Muscular Atrophy, Spinal
PubMed: 28634552
DOI: 10.1155/2017/6509493 -
Current Opinion in Neurobiology Dec 2013During development, the migration of specific neuronal subtypes is required for the correct establishment of neural circuits. In mice and zebrafish, facial branchiomotor... (Review)
Review
During development, the migration of specific neuronal subtypes is required for the correct establishment of neural circuits. In mice and zebrafish, facial branchiomotor (FBM) neurons undergo a tangential migration from rhombomere 4 caudally through the hindbrain. Recent advances in the field have capitalized on genetic studies in zebrafish and mouse, and high-resolution time-lapse imaging in zebrafish. Planar cell polarity signaling has emerged as a critical conserved factor in FBM neuron migration, functioning both within the neurons and their environment. In zebrafish, migration depends on specialized 'pioneer' neurons to lead follower FBM neurons through the hindbrain, and on interactions with structural components including pre-laid axon tracts and the basement membrane. Despite fundamental conservation, species-specific differences in migration mechanisms are being uncovered.
Topics: Animals; Cell Movement; Facial Nerve; Humans; Motor Neurons; Neurogenesis
PubMed: 24090878
DOI: 10.1016/j.conb.2013.09.001 -
Respiratory Physiology & Neurobiology Jul 2019Respiratory motor neuron death arises from multiple neurodegenerative and traumatic neuromuscular disorders. Despite motor neuron death, compensatory mechanisms minimize... (Review)
Review
Respiratory motor neuron death arises from multiple neurodegenerative and traumatic neuromuscular disorders. Despite motor neuron death, compensatory mechanisms minimize its functional impact by harnessing intrinsic mechanisms of compensatory respiratory plasticity. However, the capacity for compensation eventually reaches limits and pathology ensues. Initially, challenges to the system such as increased metabolic demand reveal sub-clinical pathology. With greater motor neuron loss, the eventual result is de-compensation, ventilatory failure, ventilator dependence and then death. In this brief review, we discuss recent advances in our understanding of mechanisms giving rise to compensatory respiratory plasticity in response to respiratory motor neuron death including: 1) increased central respiratory drive, 2) plasticity in synapses on spared phrenic motor neurons, 3) enhanced neuromuscular transmission and 4) shifts in respiratory muscle utilization from more affected to less affected motor pools. Some of these compensatory mechanisms may prolong breathing function, but hasten the demise of surviving motor neurons. Improved understanding of these mechanisms and their impact on survival of spared motor neurons will guide future efforts to develop therapeutic interventions that preserve respiratory function with neuromuscular injury/disease.
Topics: Animals; Cell Death; Humans; Motor Neurons; Neuromuscular Diseases; Neuronal Plasticity; Phrenic Nerve; Recruitment, Neurophysiological; Respiration; Respiratory Center; Respiratory Muscles
PubMed: 30625378
DOI: 10.1016/j.resp.2019.01.001 -
Developmental Neurobiology Oct 2022Motor neuron disease (MND), including amyotrophic lateral sclerosis, spinal muscular atrophy and others, involved the upper or lower motor neurons selective loss, is... (Review)
Review
Motor neuron disease (MND), including amyotrophic lateral sclerosis, spinal muscular atrophy and others, involved the upper or lower motor neurons selective loss, is characterized by neurodegeneration and neuroinflammation, in conjunction with microglia. We summarized that pathways and key mediators are associated with microglia, such as fractalkine signaling, purinergic signaling, NF-κB signaling, p38 MAPK signaling, TREM2-APOE signaling, ROCK signaling, C1q signaling, and Ion channel, which are involved in the activation, proliferation, and inflammation of microglia. This review aims to identify the microglia-related molecular target and explore potential treatment strategies for MND based on that target.
Topics: Humans; Microglia; Superoxide Dismutase; Motor Neuron Disease; Amyotrophic Lateral Sclerosis; Motor Neurons
PubMed: 36309345
DOI: 10.1002/dneu.22905