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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 -
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 -
Journal of Cellular and Molecular... Feb 2018Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the selective death of lower motor neurons in the brain stem and... (Review)
Review
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by the selective death of lower motor neurons in the brain stem and spinal cord. SMA is caused by mutations in the survival motor neuron 1 gene (SMN1), leading to the reduced expression of the full-length SMN protein. microRNAs (miRNAs) are small RNAs that regulate post-transcriptional gene expression. Recent findings have suggested an important role for miRNAs in the pathogenesis of motor neuron diseases, including SMA. Motor neuron-specific miRNA dysregulation in SMA might be implicated in their selective vulnerability. In this study, we discuss recent findings regarding the consequences of SMN defects on miRNAs and their target mRNAs in motor neurons. Taken together, these data suggest that cell-specific changes in miRNAs are not only involved in the SMA motor neuron phenotype but can also be used as biomarkers and therapeutic targets.
Topics: Animals; Biomarkers; Cell Death; Humans; MicroRNAs; Molecular Targeted Therapy; Motor Neurons; Muscular Atrophy, Spinal
PubMed: 29160009
DOI: 10.1111/jcmm.13450 -
Brain and Behavior Dec 2021Split phenotypes, (split hand, elbow, leg, and foot), are probably unique to ALS, and are characterized by having a shared peripheral input of both affected and... (Review)
Review
BACKGROUND
Split phenotypes, (split hand, elbow, leg, and foot), are probably unique to ALS, and are characterized by having a shared peripheral input of both affected and unaffected muscles. This implies an anatomical origin rostral to the spinal cord, primarily within the cerebral cortex. Therefore, split phenotypes are a potential marker of ALS upper motor neuron pathology. However, to date, reports documenting upper motor neuron dysfunction in split phenotypes have been limited to using transcranial magnetic stimulation and cortical threshold tracking techniques. Here, we consider several other potential methodologies that could confirm a primary upper motor neuron pathology in split phenotypes.
METHODS
We review the potential of: 1. measuring the compound excitatory post-synaptic potential recorded from a single activated motor unit, 2. cortical-muscular coherence, and 3. new advanced modalities of neuroimaging (high-resolution imaging protocols, ultra-high field MRI platforms [7T], and novel Non-Gaussian diffusion models).
CONCLUSIONS
We propose that muscles involved in split phenotypes are those functionally involved in the human motor repertoire used particularly in complex activities. Their anterior horn cells receive the strongest corticomotoneuronal input. This is also true of the weakest muscles that are the earliest to be affected in ALS. Descriptions of split hand in non-ALS cases and proposals that peripheral nerve or muscle dysfunction may be causative are contentious. Only a few carefully controlled cases of each form of split phenotype, using upper motor neuron directed methodologies, are necessary to prove our postulate.
Topics: Amyotrophic Lateral Sclerosis; Humans; Motor Neurons; Neuroimaging; Phenotype; Transcranial Magnetic Stimulation
PubMed: 34710283
DOI: 10.1002/brb3.2403 -
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 Drug Targets Oct 2010Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur... (Review)
Review
Lower motor neuron (LMN) degeneration occurs in several diseases that affect patients from neonates to elderly and can either be genetically transmitted or occur sporadically. Among diseases involving LMN degeneration, spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (Kennedy's disease, SBMA) are pure genetic diseases linked to loss of the SMN gene (SMA) or expansion of a polyglutamine tract in the androgen receptor gene (SBMA) while amyotrophic lateral sclerosis (ALS) can either be of genetic origin or occur sporadically. In this review, our aim is to put forward the hypothesis that muscle fiber atrophy and weakness might not be a simple collateral damage of LMN degeneration, but instead that muscle fibers may be the site of crucial pathogenic events in these diseases. In SMA, the SMN gene was shown to be required for muscle structure and strength as well as for neuromuscular junction formation, and a subset of SMA patients develop myopathic pathology. In SBMA, the occurrence of myopathic histopathology in patients and animal models, along with neuromuscular phenotype of animal models expressing the androgen receptor in muscle only has lead to the proposal that SBMA may indeed be a muscle disease. Lastly, in ALS, at least part of the phenotype might be explained by pathogenic events occuring in skeletal muscle. Apart from its potential pathogenic role, skeletal muscle pathophysiological events might be a target for treatments and/or be a preferential route for targeting motor neurons.
Topics: Animals; Drug Delivery Systems; Humans; Motor Neuron Disease; Motor Neurons; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy
PubMed: 20840067
DOI: 10.2174/1389450111007011250 -
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 -
Proceedings of the National Academy of... Dec 2016The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models...
The molecular and cellular basis of selective motor neuron (MN) vulnerability in amyotrophic lateral sclerosis (ALS) is not known. In genetically distinct mouse models of familial ALS expressing mutant superoxide dismutase-1 (SOD1), TAR DNA-binding protein 43 (TDP-43), and fused in sarcoma (FUS), we demonstrate selective degeneration of alpha MNs (α-MNs) and complete sparing of gamma MNs (γ-MNs), which selectively innervate muscle spindles. Resistant γ-MNs are distinct from vulnerable α-MNs in that they lack synaptic contacts from primary afferent (I) fibers. Elimination of these synapses protects α-MNs in the SOD1 mutant, implicating this excitatory input in MN degeneration. Moreover, reduced I activation by targeted reduction of γ-MNs in SOD1 mutants delays symptom onset and prolongs lifespan, demonstrating a pathogenic role of surviving γ-MNs in ALS. This study establishes the resistance of γ-MNs as a general feature of ALS mouse models and demonstrates that synaptic excitation of MNs within a complex circuit is an important determinant of relative vulnerability in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; DNA-Binding Proteins; Disease Models, Animal; Female; Genotype; Male; Mice; Mice, Transgenic; Motor Neurons; Motor Neurons, Gamma; Muscles; Mutation; Neurons, Afferent; Proprioception; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1; Synapses
PubMed: 27930290
DOI: 10.1073/pnas.1605210113 -
Drug Discovery Today Mar 2018Amyotrophic lateral sclerosis (ALS) is a complex disease, that affects the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a complex disease, that affects the motor neuron circuitry. After consecutive failures in clinical trials for the past 20 years, edaravone was recently approved as the second drug for ALS. This generated excitement in the field revealed the need to improve preclinical assays for continued success. Here, we focus on the importance and relevance of upper motor neuron (UMN) pathology in ALS, and discuss how incorporation of UMN survival in preclinical assays will improve inclusion criteria for clinical trials and expedite the drug discovery effort in ALS and related motor neuron diseases.
Topics: Amyotrophic Lateral Sclerosis; Animals; Clinical Trials as Topic; Drug Discovery; Humans; Motor Neurons; Pharmaceutical Preparations
PubMed: 29331501
DOI: 10.1016/j.drudis.2018.01.027 -
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