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Why do motor neurons degenerate? Actualization in the pathogenesis of amyotrophic lateral sclerosis.Neurologia 2019Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin... (Review)
Review
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons. Although a small proportion of ALS cases are familial in origin and linked to mutations in specific genes, most cases are sporadic and have a multifactorial aetiology. Some recent studies have increased our knowledge of ALS pathogenesis and raised the question of whether this disorder is a proteinopathy, a ribonucleopathy, an axonopathy, or a disease related to the neuronal microenvironment.
DEVELOPMENT
This article presents a review of ALS pathogenesis. To this end, we have reviewed published articles describing either ALS patients or ALS animal models and we discuss how the main cellular pathways (gene processing, protein metabolism, oxidative stress, axonal transport, relationship with neuronal microenvironment) may be involved in motor neurons degeneration.
CONCLUSIONS
ALS pathogenesis has not been fully elucidated. Recent studies suggest that although initial triggers may differ among patients, the final motor neurons degeneration mechanisms are similar in most patients once the disease is fully established.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Humans; Motor Neurons
PubMed: 26853842
DOI: 10.1016/j.nrl.2015.12.001 -
Current Protocols in Pharmacology Jun 2015Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease affecting upper and lower motor neurons in the central nervous system. Patients with ALS develop extensive muscle wasting and atrophy leading to paralysis and death 3 to 5 years after disease onset. The condition may be familial (fALS 10%) or sporadic ALS (sALS, 90%). The large majority of fALS cases are due to genetic mutations in the Superoxide dismutase 1 gene (SOD1, 15% of fALS) and repeat nucleotide expansions in the gene encoding C9ORF72 (∼ 40% to 50% of fALS and ∼ 10% of sALS). Studies suggest that ALS is mediated through aberrant protein homeostasis (i.e., ER stress and autophagy) and/or changes in RNA processing (as in all non-SOD1-mediated ALS). In all of these cases, animal models suggest that the disorder is mediated non-cell autonomously, i.e., not only motor neurons are involved, but glial cells including microglia, astrocytes, and oligodendrocytes, and other neuronal subpopulations are also implicated in the pathogenesis. Provided in this unit is a review of ALS rodent models, including discussion of their relative advantages and disadvantages. Emphasis is placed on correlating the model phenotype with the human condition and the utility of the model for defining the disease process. Information is also presented on RNA processing studies in ALS research, with particular emphasis on the newest ALS rodent models.
Topics: Amyotrophic Lateral Sclerosis; Animals; Central Nervous System; DNA-Binding Proteins; Disease Models, Animal; Endoplasmic Reticulum Stress; Humans; Mice; Mice, Knockout; Mice, Neurologic Mutants; Mice, Transgenic; Motor Neurons; Mutation; Nerve Tissue Proteins; Promoter Regions, Genetic; RNA Processing, Post-Transcriptional; Rats; Rats, Mutant Strains; Rats, Transgenic; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 26344214
DOI: 10.1002/0471141755.ph0567s69 -
Brain : a Journal of Neurology Nov 2023Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with... (Review)
Review
Amyotrophic lateral sclerosis (ALS), the major adult-onset motor neuron disease, has been viewed almost exclusively as a disease of upper and lower motor neurons, with muscle changes interpreted as a consequence of the progressive loss of motor neurons and neuromuscular junctions. This has led to the prevailing view that the involvement of muscle in ALS is only secondary to motor neuron loss. Skeletal muscle and motor neurons reciprocally influence their respective development and constitute a single functional unit. In ALS, multiple studies indicate that skeletal muscle dysfunction might contribute to progressive muscle weakness, as well as to the final demise of neuromuscular junctions and motor neurons. Furthermore, skeletal muscle has been shown to participate in disease pathogenesis of several monogenic diseases closely related to ALS. Here, we move the narrative towards a better appreciation of muscle as a contributor of disease in ALS. We review the various potential roles of skeletal muscle cells in ALS, from passive bystanders to active players in ALS pathophysiology. We also compare ALS to other motor neuron diseases and draw perspectives for future research and treatment.
Topics: Adult; Humans; Amyotrophic Lateral Sclerosis; Motor Neurons; Muscle, Skeletal; Neuromuscular Junction; Muscle Weakness
PubMed: 37327376
DOI: 10.1093/brain/awad202 -
Cells May 2023Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.
Topics: Humans; Amyotrophic Lateral Sclerosis; Riluzole; Motor Neurons; Biomarkers; Disease Progression
PubMed: 37296644
DOI: 10.3390/cells12111523 -
Nature Neuroscience Apr 2016Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis... (Review)
Review
Directing the differentiation of induced pluripotent stem cells into motor neurons has allowed investigators to develop new models of amyotrophic lateral sclerosis (ALS). However, techniques vary between laboratories and the cells do not appear to mature into fully functional adult motor neurons. Here we discuss common developmental principles of both lower and upper motor neuron development that have led to specific derivation techniques. We then suggest how these motor neurons may be matured further either through direct expression or administration of specific factors or coculture approaches with other tissues. Ultimately, through a greater understanding of motor neuron biology, it will be possible to establish more reliable models of ALS. These in turn will have a greater chance of validating new drugs that may be effective for the disease.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Differentiation; Cells, Cultured; Coculture Techniques; Humans; Induced Pluripotent Stem Cells; Motor Neurons
PubMed: 27021939
DOI: 10.1038/nn.4273 -
Neuron Mar 2017Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review... (Review)
Review
Autophagy is a conserved pathway that delivers cytoplasmic contents to the lysosome for degradation. Here we consider its roles in neuronal health and disease. We review evidence from mouse knockout studies demonstrating the normal functions of autophagy as a protective factor against neurodegeneration associated with intracytoplasmic aggregate-prone protein accumulation as well as other roles, including in neuronal stem cell differentiation. We then describe how autophagy may be affected in a range of neurodegenerative diseases. Finally, we describe how autophagy upregulation may be a therapeutic strategy in a wide range of neurodegenerative conditions and consider possible pathways and druggable targets that may be suitable for this objective.
Topics: Animals; Autophagy; Humans; Lysosomes; Motor Neurons; Neurodegenerative Diseases; Proteins; Signal Transduction
PubMed: 28279350
DOI: 10.1016/j.neuron.2017.01.022 -
Brain Research Bulletin Jun 2020Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper motor neurons (UMN) and lower motor neurons (LMN). Disease affects people all over the world and is more prevalent in men. Patients with ALS develop extensive muscle wasting, paralysis and ultimately death, with a median survival of usually fewer than five years after disease onset. ALS may be sporadic (sALS, 90%) or familial (fALS, 10%). The large majority of fALS cases are associated with genetic alterations, which are mainly related to the genes SOD1, TDP-43, FUS, and C9ORF72. In vitro and in vivo models have helped elucidate ALS etiology and pathogenesis, as well as its molecular, cellular, and physiological mechanisms. Many studies in cell cultures and animal models, such as Caenorhabditis elegans, Drosophila melanogaster, zebrafish, rodents, and non-human primates have been performed to clarify the relationship of these genes to ALS disease. However, there are inherent limitations to consider when using experimental models. In this review, we provide an updated overview of the most used in vitro and in vivo studies that have contributed to a better understanding of the different ALS pathogenic mechanisms.
Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Humans; Motor Neurons; Superoxide Dismutase-1
PubMed: 32247802
DOI: 10.1016/j.brainresbull.2020.03.012 -
Brain : a Journal of Neurology Jun 2022CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated...
CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (P < 0.001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.
Topics: Cerebellar Ataxia; Gliosis; Humans; Motor Neurons; Primary Dysautonomias; Reflex, Abnormal
PubMed: 34927205
DOI: 10.1093/brain/awab449 -
European Journal of Applied Physiology Mar 2021The initial increases in force production with resistance training are thought to be primarily underpinned by neural adaptations. This notion is firmly supported by... (Review)
Review
The initial increases in force production with resistance training are thought to be primarily underpinned by neural adaptations. This notion is firmly supported by evidence displaying motor unit adaptations following resistance training; however, the precise locus of neural adaptation remains elusive. The purpose of this review is to clarify and critically discuss the literature concerning the site(s) of putative neural adaptations to short-term resistance training. The proliferation of studies employing non-invasive stimulation techniques to investigate evoked responses have yielded variable results, but generally support the notion that resistance training alters intracortical inhibition. Nevertheless, methodological inconsistencies and the limitations of techniques, e.g. limited relation to behavioural outcomes and the inability to measure volitional muscle activity, preclude firm conclusions. Much of the literature has focused on the corticospinal tract; however, preliminary research in non-human primates suggests reticulospinal tract is a potential substrate for neural adaptations to resistance training, though human data is lacking due to methodological constraints. Recent advances in technology have provided substantial evidence of adaptations within a large motor unit population following resistance training. However, their activity represents the transformation of afferent and efferent inputs, making it challenging to establish the source of adaptation. Whilst much has been learned about the nature of neural adaptations to resistance training, the puzzle remains to be solved. Additional analyses of motoneuron firing during different training regimes or coupling with other methodologies (e.g., electroencephalography) may facilitate the estimation of the site(s) of neural adaptations to resistance training in the future.
Topics: Adaptation, Physiological; Evoked Potentials, Motor; Humans; Motor Neurons; Resistance Training
PubMed: 33355714
DOI: 10.1007/s00421-020-04567-3 -
Cells Jan 2022Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and one of the most common genetic causes of infant death. It is characterized by... (Review)
Review
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder and one of the most common genetic causes of infant death. It is characterized by progressive weakness of the muscles, loss of ambulation, and death from respiratory complications. SMA is caused by the homozygous deletion or mutations in the survival of the motor neuron 1 () gene. Humans, however, have a nearly identical copy of known as the gene. The severity of the disease correlates inversely with the number of copies present. cannot completely compensate for the loss of in SMA patients because it can produce only a fraction of functional SMN protein. SMN protein is ubiquitously expressed in the body and has a variety of roles ranging from assembling the spliceosomal machinery, autophagy, RNA metabolism, signal transduction, cellular homeostasis, DNA repair, and recombination. Motor neurons in the anterior horn of the spinal cord are extremely susceptible to the loss of SMN protein, with the reason still being unclear. Due to the ability of the gene to produce small amounts of functional SMN, two FDA-approved treatment strategies, including an antisense oligonucleotide (AON) nusinersen and small-molecule risdiplam, target to produce more functional SMN. On the other hand, Onasemnogene abeparvovec (brand name Zolgensma) is an FDA-approved adeno-associated vector 9-mediated gene replacement therapy that can deliver a copy of the human In this review, we summarize the SMA etiology, the role of SMN, and discuss the challenges of the therapies that are approved for SMA treatment.
Topics: Homozygote; Humans; Infant; Motor Neurons; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Sequence Deletion
PubMed: 35159227
DOI: 10.3390/cells11030417