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International Journal of Molecular... Dec 2022The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS... (Review)
Review
Amyotrophic Lateral Sclerosis Pathoetiology and Pathophysiology: Roles of Astrocytes, Gut Microbiome, and Muscle Interactions via the Mitochondrial Melatonergic Pathway, with Disruption by Glyphosate-Based Herbicides.
The pathoetiology and pathophysiology of motor neuron loss in amyotrophic lateral sclerosis (ALS) are still to be determined, with only a small percentage of ALS patients having a known genetic risk factor. The article looks to integrate wider bodies of data on the biological underpinnings of ALS, highlighting the integrative role of alterations in the mitochondrial melatonergic pathways and systemic factors regulating this pathway across a number of crucial hubs in ALS pathophysiology, namely glia, gut, and the muscle/neuromuscular junction. It is proposed that suppression of the mitochondrial melatonergic pathway underpins changes in muscle brain-derived neurotrophic factor, and its melatonergic pathway mimic, N-acetylserotonin, leading to a lack of metabolic trophic support at the neuromuscular junction. The attenuation of the melatonergic pathway in astrocytes prevents activation of toll-like receptor agonists-induced pro-inflammatory transcription factors, NF-kB, and yin yang 1, from having a built-in limitation on inflammatory induction that arises from their synchronized induction of melatonin release. Such maintained astrocyte activation, coupled with heightened microglia reactivity, is an important driver of motor neuron susceptibility in ALS. Two important systemic factors, gut dysbiosis/permeability and pineal melatonin mediate many of their beneficial effects via their capacity to upregulate the mitochondrial melatonergic pathway in central and systemic cells. The mitochondrial melatonergic pathway may be seen as a core aspect of cellular function, with its suppression increasing reactive oxygen species (ROS), leading to ROS-induced microRNAs, thereby altering the patterning of genes induced. It is proposed that the increased occupational risk of ALS in farmers, gardeners, and sportsmen and women is intimately linked to exposure, whilst being physically active, to the widely used glyphosate-based herbicides. This has numerous research and treatment implications.
Topics: Humans; Amyotrophic Lateral Sclerosis; Astrocytes; Gastrointestinal Microbiome; Melatonin; Muscles; Reactive Oxygen Species; Herbicides; Glyphosate
PubMed: 36614029
DOI: 10.3390/ijms24010587 -
Scientific Reports Jan 2022Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower...
Mutations in superoxide dismutase 1 gene (SOD1) are linked to amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder predominantly affecting upper and lower motor neurons. The clinical phenotype of ALS shows inter- and intrafamilial heterogeneity. The aim of the study was to analyze the relations between individual SOD1 mutations and the clinical presentation using in silico methods to assess the SOD1 mutations severity. We identified SOD1 causative variants in a group of 915 prospectively tested consecutive Polish ALS patients from a neuromuscular clinical center, performed molecular modeling of mutated SOD1 proteins and in silico analysis of mutation impact on clinical phenotype and survival analysis of associations between mutations and hazard of clinical end-points. Fifteen SOD1 mutations were identified in 21.1% familial and 2.3% sporadic ALS cases. Their effects on SOD1 protein structure and functioning inferred from molecular modeling and in silico analyses correlate well with the clinical data. Molecular modeling results support the hypothesis that folding intermediates rather than mature SOD1 protein give rise to the source of cytotoxic conformations in ALS. Significant associations between type of mutation and clinical end-points were found.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Middle Aged; Models, Molecular; Mutation; Mutation Rate; Patient Acuity; Phenotype; Poland; Prognosis; Protein Conformation; Protein Folding; Structure-Activity Relationship; Superoxide Dismutase-1
PubMed: 34996976
DOI: 10.1038/s41598-021-03891-8 -
Atencion Primaria Dec 2021Amyotrophic Lateral Sclerosis (ALS) is a rare disease in primary care (PC), it represents a challenge for the family doctor, especially in home care. (Observational Study)
Observational Study
UNLABELLED
Amyotrophic Lateral Sclerosis (ALS) is a rare disease in primary care (PC), it represents a challenge for the family doctor, especially in home care.
OBJECTIVE
To know the incidence and prevalence of ALS in an area of ??PA management, the clinical characteristics and use of health resources.
DESIGN
Observational study.
LOCATION
PC-Direction Costa de Ponent, South Metropolitan Health Region, Barcelona, Catalonia, Spain.
PARTICIPANTS
Patients with ALS ≥18 years diagnosed until 03/01/2017. Main measurements Age, sex, characteristics: form of appearance (spinal, bulbar, others), interval between onset of symptoms and diagnosis, percutaneous gastrostomy carriers, ventilation non-invasive or invasive. Identification in PC as a Complex Chronic Patient or with palliative needs (CCP). Inclusion in home care programs (PAD). Model of attention hospitable.
RESULTS
81 patients, mean age 65.6 years (± 11.7), men 49.4%. Shape of onset: spinal 69%, bulbar 21%, another 4%. Interval between the onset of symptoms and diagnosis 12 months. Identified as a CCP 13.6%, 29 patients (35.8%) included in PAD. Attended in comprehensive hospital model 79 patients (97.5%). Prevalence 6.1/100,000 inhabitants in 2017. Annual incidence between 1.2 cases/100,000 inhabitants/year in 2012 and 3.5 cases/100,000 inhabitants/year in 2016.
CONCLUSIONS
The use of percutaneous gastrostomy in ALS favors the identification as CCP or with palliative needs and inclusion in PAD. The use of non-invasive ventilation favors inclusion in PAD. The incidence and prevalence data for ALS are higher than those described above in the same area. Early identification is necessary of these patients in the chronic care models in PC teams.
Topics: Aged; Amyotrophic Lateral Sclerosis; Female; Home Care Services; Humans; Male; Middle Aged; Primary Health Care; Spain
PubMed: 34509895
DOI: 10.1016/j.aprim.2021.102158 -
International Journal of Molecular... Oct 2022Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, lethal, and degenerative disease of motor neurons for which there is no treatment currently available [...].
Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, lethal, and degenerative disease of motor neurons for which there is no treatment currently available [...].
Topics: Humans; Amyotrophic Lateral Sclerosis; Motor Neurons
PubMed: 36292944
DOI: 10.3390/ijms232012069 -
Neurobiology of Disease Jul 2020Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons throughout the brain and spinal cord progressively degenerate resulting in...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons throughout the brain and spinal cord progressively degenerate resulting in muscle atrophy, paralysis and death. Recent studies using animal models of ALS implicate multiple cell-types (e.g., astrocytes and microglia) in ALS pathogenesis in the spinal motor systems. To ascertain cellular vulnerability and cell-type specific mechanisms of ALS in the brainstem that orchestrates oral-motor functions, we conducted parallel single cell RNA sequencing (scRNA-seq) analysis using the high-throughput Drop-seq method. We isolated 1894 and 3199 cells from the brainstem of wildtype and mutant SOD1 symptomatic mice respectively, at postnatal day 100. We recovered major known cell types and neuronal subpopulations, such as interneurons and motor neurons, and trigeminal ganglion (TG) peripheral sensory neurons, as well as, previously uncharacterized interneuron subtypes. We found that the majority of the cell types displayed transcriptomic alterations in ALS mice. Differentially expressed genes (DEGs) of individual cell populations revealed cell-type specific alterations in numerous pathways, including previously known ALS pathways such as inflammation (in microglia), stress response (ependymal and an uncharacterized cell population), neurogenesis (astrocytes, oligodendrocytes, neurons), synapse organization and transmission (microglia, oligodendrocyte precursor cells, and neuronal subtypes), and mitochondrial function (uncharacterized cell populations). Other cell-type specific processes altered in SOD1 mutant brainstem include those from motor neurons (axon regeneration, voltage-gated sodium and potassium channels underlying excitability, potassium ion transport), trigeminal sensory neurons (detection of temperature stimulus involved in sensory perception), and cellular response to toxic substances (uncharacterized cell populations). DEGs consistently altered across cell types (e.g., Malat1), as well as cell-type specific DEGs, were identified. Importantly, DEGs from various cell types overlapped with known ALS genes from the literature and with top hits from an existing human ALS genome-wide association study (GWAS), implicating the potential cell types in which the ALS genes function with ALS pathogenesis. Our molecular investigation at single cell resolution provides comprehensive insights into the cell types, genes and pathways altered in the brainstem in a widely used ALS mouse model.
Topics: Amyotrophic Lateral Sclerosis; Animals; Brain Stem; Female; Mice, Transgenic; Mutation; Neurons; Sequence Analysis, RNA; Signal Transduction; Single-Cell Analysis; Superoxide Dismutase-1; Transcriptome
PubMed: 32360664
DOI: 10.1016/j.nbd.2020.104877 -
Annals of Clinical and Translational... Nov 2023Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite...
OBJECTIVE
Advances in amyotrophic lateral sclerosis (ALS) gene discovery, ongoing gene therapy trials, and patient demand have driven increased use of ALS genetic testing. Despite this progress, the offer of genetic testing to persons with ALS is not yet "standard of care." Our primary goal is to develop clinical ALS genetic counseling and testing guidelines to improve and standardize genetic counseling and testing practice among neurologists, genetic counselors or any provider caring for persons with ALS.
METHODS
Core clinical questions were identified and a rapid review performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) 2015 method. Guideline recommendations were drafted and the strength of evidence for each recommendation was assessed by combining two systems: the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) System and the Evaluation of Genomic Applications in Practice and Prevention (EGAPP). A modified Delphi approach was used to reach consensus among a group of content experts for each guideline statement.
RESULTS
A total of 35 guideline statements were developed. In summary, all persons with ALS should be offered single-step genetic testing, consisting of a C9orf72 assay, along with sequencing of SOD1, FUS, and TARDBP, at a minimum. The key education and genetic risk assessments that should be provided before and after testing are delineated. Specific guidance regarding testing methods and reporting for C9orf72 and other genes is provided for commercial laboratories.
INTERPRETATION
These evidence-based, consensus guidelines will support all stakeholders in the ALS community in navigating benefits and challenges of genetic testing.
Topics: Humans; Amyotrophic Lateral Sclerosis; C9orf72 Protein; Systematic Reviews as Topic; Meta-Analysis as Topic; Genetic Testing; Counseling
PubMed: 37691292
DOI: 10.1002/acn3.51895 -
Developmental Neurobiology Jan 2022Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper... (Review)
Review
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.
Topics: Amyotrophic Lateral Sclerosis; Central Nervous System; Humans; Membrane Glycoproteins; Microglia; Motor Neurons; Neurodegenerative Diseases; Receptors, Immunologic
PubMed: 34874625
DOI: 10.1002/dneu.22864 -
International Journal of Molecular... Apr 2021Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a... (Review)
Review
Over the years, researchers have leveraged a host of different in vivo models in order to dissect amyotrophic lateral sclerosis (ALS), a neurodegenerative/neuroinflammatory disease that is heterogeneous in its clinical presentation and is multigenic, multifactorial and non-cell autonomous. These models include both vertebrates and invertebrates such as yeast, worms, flies, zebrafish, mice, rats, guinea pigs, dogs and, more recently, non-human primates. Despite their obvious differences and peculiarities, only the concurrent and comparative analysis of these various systems will allow the untangling of the causes and mechanisms of ALS for finally obtaining new efficacious therapeutics. However, harnessing these powerful organisms poses numerous challenges. In this context, we present here an updated and comprehensive review of how eukaryotic unicellular and multicellular organisms that reproduce a few of the main clinical features of the disease have helped in ALS research to dissect the pathological pathways of the disease insurgence and progression. We describe common features as well as discrepancies among these models, highlighting new insights and emerging roles for experimental organisms in ALS.
Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Disease Models, Animal; Dogs; Guinea Pigs; Humans; Mice; Neurodegenerative Diseases; Rats; Zebrafish
PubMed: 33921446
DOI: 10.3390/ijms22083977 -
Amyotrophic Lateral Sclerosis &... Aug 2019Successful treatment of neurodegenerative disease may hinge on early therapeutic intervention. This requires an understanding of early/pre-symptomatic disease, a need... (Review)
Review
Successful treatment of neurodegenerative disease may hinge on early therapeutic intervention. This requires an understanding of early/pre-symptomatic disease, a need that is underscored by advances in antisense oligonucleotide, and viral-vector-based gene therapies. In amyotrophic lateral sclerosis (ALS), the study of pre-symptomatic disease requires a cohesive conceptual framework for describing this phase of disease. Informed by the literature in other neurodegenerative diseases and extensive personal experience, a model is proposed that distinguishes ALS as a clinical syndrome from ALS as a disease, and characterizes pre-symptomatic ALS as having two identifiable stages: pre-manifest and prodromal. The unique and critical importance of biomarker development is articulated and an operational definition of phenoconversion is provided. It is hoped that this framework will accelerate collective efforts to study pre-symptomatic ALS, and aid in the design and implementation of an early intervention- or disease-prevention trial.
Topics: Amyotrophic Lateral Sclerosis; Animals; Asymptomatic Diseases; Biomarkers; Humans
PubMed: 30892087
DOI: 10.1080/21678421.2019.1587634 -
International Journal of Molecular... Apr 2021Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neuron degeneration leads to muscle weakness, progressive paralysis, and death within... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease wherein motor neuron degeneration leads to muscle weakness, progressive paralysis, and death within 3-5 years of diagnosis. Currently, the cause of ALS is unknown but, as with several neurodegenerative diseases, the potential role of neuroinflammation has become an increasingly popular hypothesis in ALS research. Indeed, upregulation of neuroinflammatory factors have been observed in both ALS patients and animal models. One such factor is the inflammatory inducer NF-κB. Besides its connection to inflammation, NF-κB activity can be linked to several genes associated to familial forms of ALS, and many of the environmental risk factors of the disease stimulate NF-κB activation. Collectively, this has led many to hypothesize that NF-κB proteins may play a role in ALS pathogenesis. In this review, we discuss the genetic and environmental connections between NF-κB and ALS, as well as how this pathway may affect different CNS cell types, and finally how this may lead to motor neuron degeneration.
Topics: Alleles; Amyotrophic Lateral Sclerosis; Animals; Biomarkers; Disease Susceptibility; Environment; Enzyme Activation; Genetic Predisposition to Disease; Genetic Variation; Humans; Microglia; NF-kappa B; Neurons; Oligodendroglia
PubMed: 33918092
DOI: 10.3390/ijms22083875