scholarly journals Progress in Clinical Neurosciences: The Evidence for ALS as a Multisystems Disorder of Limited Phenotypic Expression

2001 ◽  
Vol 28 (4) ◽  
pp. 283-298 ◽  
Author(s):  
Michael J. Strong
Keyword(s):  
Motor Neurons ◽  
Phenotypic Variability ◽  
Phenotypic Expression ◽  
Disease Process ◽  
Cellular Level ◽  
Central Component ◽  
Biological Processes ◽  
Motor Neuron Degeneration ◽  
Biological Heterogeneity ◽  
Lateral Sclerosis

Traditionally, amyotrophic lateral sclerosis (ALS) is considered to be a unique neurodegeneration disorder in which motor neurons are selectively vulnerable to a single disease process. Our current understanding of ALS, however, suggests that this is far too limited an approach. While motor neuron degeneration remains the central component to this process, there is considerable phenotypic variability including broad ranges in survivorship and the presence or absence of cognitive impairment. The number of familial variants of ALS for which unique genetic linkage has been identified is increasing, attesting further to the biological heterogeneity of the disorder. At the cellular level, derangements in cytoskeletal protein and glutamate metabolism, mitochondrial function, and in glial interactions are clearly evident. When considered in this fashion, ALS can be justifiably considered a disorder of multiple biological processes sharing in common the degeneration of motor neurons.

scholarly journals The multifaceted role of kinases in amyotrophic lateral sclerosis: genetic, pathological and therapeutic implications

Brain ◽  
2020 ◽  
Vol 143 (6) ◽  
pp. 1651-1673 ◽  
Author(s):  
Wenting Guo ◽  
Tijs Vandoorne ◽  
Jolien Steyaert ◽  
Kim A Staats ◽  
Ludo Van Den Bosch
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Disease Process ◽  
Multiple Roles ◽  
Motor Neuron Degeneration ◽  
Therapeutic Implications ◽  
Degenerative Disorder ◽  
Amyotrophic Lateral Sclerosis Pathogenesis ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis is the most common degenerative disorder of motor neurons in adults. As there is no cure, thousands of individuals who are alive at present will succumb to the disease. In recent years, numerous causative genes and risk factors for amyotrophic lateral sclerosis have been identified. Several of the recently identified genes encode kinases. In addition, the hypothesis that (de)phosphorylation processes drive the disease process resulting in selective motor neuron degeneration in different disease variants has been postulated. We re-evaluate the evidence for this hypothesis based on recent findings and discuss the multiple roles of kinases in amyotrophic lateral sclerosis pathogenesis. We propose that kinases could represent promising therapeutic targets. Mainly due to the comprehensive regulation of kinases, however, a better understanding of the disturbances in the kinome network in amyotrophic lateral sclerosis is needed to properly target specific kinases in the clinic.

scholarly journals Senolytics: A Novel Strategy for Neuroprotection in ALS?

2021 ◽  
Vol 22 (21) ◽  
pp. 12078
Author(s):  
Alexandra Maximova ◽  
Eryn L. Werry ◽  
Michael Kassiou
Keyword(s):  
Motor Neurons ◽  
Therapeutic Strategy ◽  
Cellular Level ◽  
Proper Function ◽  
Preclinical Models ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Muscular Dysfunction ◽  
Novel Strategy ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

scholarly journals Neuropathologic description of CHCHD10 mutated amyotrophic lateral sclerosis

2020 ◽  
Vol 6 (1) ◽  
pp. e394
Author(s):  
Julia L. Keith ◽  
Emily Swinkin ◽  
Andrew Gao ◽  
Samira Alminawi ◽  
Ming Zhang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Mutation Carrier ◽  
Double Immunofluorescence ◽  
Motor Neuron Degeneration ◽  
Respiratory Involvement ◽  
Sporadic Als ◽  
Immunofluorescence Labeling ◽  
Normal Controls ◽  
Lateral Sclerosis

ObjectiveTo present the postmortem neuropathologic report of a patient with a CHCHD10 mutation exhibiting an amyotrophic lateral sclerosis (ALS) clinical phenotype.MethodsA 54-year-old man without significant medical history or family history presented with arm weakness, slowly progressed over 19 years to meet the El Escorial criteria for clinically probable ALS with bulbar and respiratory involvement, and was found to have a CHCHD10 p.R15L mutation. Postmortem neuropathologic examination took place including immunohistochemical staining with CHCHD10, and double immunofluorescence combining CHCHD10 with TDP43 and neurofilament was performed and the results were compared with normal controls and sporadic ALS cases.ResultsPostmortem examination of the CHCHD10 mutation carrier showed severe loss of hypoglossal and anterior horn motor neurons, mild corticospinal tract degeneration, and a relative lack of TDP43 immunopathology. CHCHD10 immunohistochemistry for the 3 controls and the 5 sporadic ALS cases showed strong neuronal cytoplasmic and axonal labeling, with the CHCHD10 mutation carrier also having numerous CHCHD10 aggregates within their anterior horns. These aggregates may be related to the CHCHD10 aggregates recently described to cause mitochondrial degeneration and disease in a tissue-selective toxic gain-of-function fashion in a CHCHD10 knock-in mouse model. The CHCHD10 aggregates did not colocalize with TDP43 and were predominantly extracellular on double immunofluorescence labeling with neurofilament.ConclusionsThe neuropathology of CHCHD10 mutated ALS includes predominantly lower motor neuron degeneration, absent TDP43 immunopathology, and aggregates of predominantly extracellular CHCHD10, which do not contain TDP43.

scholarly journals Complexity of Generating Mouse Models to Study the Upper Motor Neurons: Let Us Shift Focus from Mice to Neurons

2019 ◽  
Vol 20 (16) ◽  
pp. 3848 ◽  
Author(s):  
Baris Genc ◽  
Oge Gozutok ◽  
P. Hande Ozdinler
Keyword(s):  
Motor Neuron ◽  
Mouse Models ◽  
Motor Neurons ◽  
Cell Biology ◽  
Neuronal Degeneration ◽  
Cellular Level ◽  
Model Systems ◽  
Special Importance ◽  
Upper Motor Neurons ◽  
Lateral Sclerosis

Motor neuron circuitry is one of the most elaborate circuitries in our body, which ensures voluntary and skilled movement that requires cognitive input. Therefore, both the cortex and the spinal cord are involved. The cortex has special importance for motor neuron diseases, in which initiation and modulation of voluntary movement is affected. Amyotrophic lateral sclerosis (ALS) is defined by the progressive degeneration of both the upper and lower motor neurons, whereas hereditary spastic paraplegia (HSP) and primary lateral sclerosis (PLS) are characterized mainly by the loss of upper motor neurons. In an effort to reveal the cellular and molecular basis of neuronal degeneration, numerous model systems are generated, and mouse models are no exception. However, there are many different levels of complexities that need to be considered when developing mouse models. Here, we focus our attention to the upper motor neurons, which are one of the most challenging neuron populations to study. Since mice and human differ greatly at a species level, but the cells/neurons in mice and human share many common aspects of cell biology, we offer a solution by focusing our attention to the affected neurons to reveal the complexities of diseases at a cellular level and to improve translational efforts.

scholarly journals Pathophysiology and Diagnosis of ALS: Insights from Advances in Neurophysiological Techniques

2019 ◽  
Vol 20 (11) ◽  
pp. 2818 ◽  
Author(s):  
Mehdi A. J. van den Bos ◽  
Nimeshan Geevasinga ◽  
Mana Higashihara ◽  
Parvathi Menon ◽  
Steve Vucic
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Clinical Phenotype ◽  
Disease Process ◽  
Disease Spread ◽  
Molecular Processes ◽  
Cortical Hyperexcitability ◽  
Upper Motor Neuron Dysfunction ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder of the motor neurons, characterized by focal onset of muscle weakness and incessant disease progression. While the presence of concomitant upper and lower motor neuron signs has been recognized as a pathognomonic feature of ALS, the pathogenic importance of upper motor neuron dysfunction has only been recently described. Specifically, transcranial magnetic stimulation (TMS) techniques have established cortical hyperexcitability as an important pathogenic mechanism in ALS, correlating with neurodegeneration and disease spread. Separately, ALS exhibits a heterogeneous clinical phenotype that may lead to misdiagnosis, particularly in the early stages of the disease process. Cortical hyperexcitability was shown to be a robust diagnostic biomarker if ALS, reliably differentiating ALS from neuromuscular mimicking disorders. The present review will provide an overview of key advances in the understanding of ALS pathophysiology and diagnosis, focusing on the importance of cortical hyperexcitability and its relationship to advances in genetic and molecular processes implicated in ALS pathogenesis.

scholarly journals Blood Biomarkers for Amyotrophic Lateral Sclerosis: Myth or Reality?

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Laura Robelin ◽  
Jose Luis Gonzalez De Aguilar
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Multiple Testing ◽  
Low Cost ◽  
Cellular Level ◽  
Point Of View ◽  
Metabolic Dysfunction ◽  
Therapeutic Trials ◽  
Electrophysiological Findings ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal condition primarily characterized by the selective loss of upper and lower motor neurons. At present, the diagnosis and monitoring of ALS is based on clinical examination, electrophysiological findings, medical history, and exclusion of confounding disorders. There is therefore an undeniable need for molecular biomarkers that could give reliable information on the onset and progression of ALS in clinical practice and therapeutic trials. From a practical point of view, blood offers a series of advantages, including easy handling and multiple testing at a low cost, that make it an ideal source of biomarkers. In this review, we revisited the findings of many studies that investigated the presence of systemic changes at the molecular and cellular level in patients with ALS. The results of these studies reflect the diversity in the pathological mechanisms contributing to disease (e.g., excitotoxicity, oxidative stress, neuroinflammation, metabolic dysfunction, and neurodegeneration, among others) and provide relatively successful evidence of the usefulness of a wide-ranging panel of molecules as potential biomarkers. More studies, hopefully internationally coordinated, would be needed, however, to translate the application of these biomarkers into benefit for patients.

scholarly journals Dysfunction of RNA/RNA-Binding Proteins in ALS Astrocytes and Microglia

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3005
Author(s):  
Simona Rossi ◽  
Mauro Cozzolino
Keyword(s):  
Motor Neurons ◽  
Binding Proteins ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Cell Types ◽  
Rna Metabolism ◽  
Causal Link ◽  
Motor Neuron Degeneration ◽  
Relevant Role ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis is a neurological disease that primarily affects motor neurons in the cortex, brainstem, and spinal cord. The process that leads to motor neuron degeneration is strongly influenced by non-motor neuronal events that occur in a variety of cell types. Among these, neuroinflammatory processes mediated by activated astrocytes and microglia play a relevant role. In recent years, it has become clear that dysregulation of essential steps of RNA metabolism, as a consequence of alterations in RNA-binding proteins (RBPs), is a central event in the degeneration of motor neurons. Yet, a causal link between dysfunctional RNA metabolism and the neuroinflammatory processes mediated by astrocytes and microglia in ALS has been poorly defined. In this review, we will discuss the available evidence showing that RBPs and associated RNA processing are affected in ALS astrocytes and microglia, and the possible mechanisms involved in these events.

scholarly journals From Hahnemann to the Physiology of the Complex Systems in Practice

2021 ◽  
Vol 17 (2) ◽  
pp. 04-04
Author(s):  
Romeu Carillo Jr ◽  
Maria Filomena Xavier Mendes ◽  
Maria Solange Gosik ◽  
Domingos José Vaz Do Cabo ◽  
Raquel Bruno Kalile ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Complex Systems ◽  
Chronic Diseases ◽  
Motor Neurons ◽  
Genetic Disorder ◽  
Self Regulation ◽  
Disease Process ◽  
Systems Model ◽  
Lateral Sclerosis ◽  
Clinical Cases

Background: Amyotrophic Lateral Sclerosis is a progressive and fatal neurodegenerative disease that affects motor neurons and has two forms, one familial and the other sporadic. Wilson´s disease is a genetic disorder, autosomal recessive, which causes changes in copper metabolism. Methodology: In this paper, the author presents two clinical cases of patients with amyotrophic lateral sclerosis (ALS) and Wilson's disease (WD), showing the evolution of each one from the beginning of the homeopathic treatment, whose prescription was based on the theory of Complex Systems of Carillo. Results and Discussion: Understanding the pathophysiology of each chronic disease, and recognizing the syndromic nature of the absolute majority of natural chronic diseases, allows us to use the most indicated drugs for every case and shows the best way to prescribe these medications. Treating chronic diseases based on clear and well-defined principles. Based in this principle, the concepts of Prioritization of Systems, related organic injury,emunctorial block and equalization are applied in both clinical cases.The identification of the latter avoids homeopathic aggravations, essential for patients in severe states. Conclusion: The theoretical bases for the understanding of clinical cases, in the Complex Systems Model of Carillo, with its 8 elements, namely: Structure (material body); Self-regulation (immaterial); Organization Pattern; Dissipation; Autopoiesis; Adaptation; Cognition and Consciousness, allow an expanded understanding of the health disease process.

scholarly journals Alterations in Tau Metabolism in ALS and ALS-FTSD

2020 ◽  
Vol 11 ◽  
Author(s):  
Michael J. Strong ◽  
Neil S. Donison ◽  
Kathryn Volkening
Keyword(s):  
Motor Neurons ◽  
Chronic Traumatic Encephalopathy ◽  
Dna Binding Protein ◽  
Tau Phosphorylation ◽  
Protein Tau ◽  
Oligomer Formation ◽  
Biological Heterogeneity ◽  
Lateral Sclerosis

There is increasing acceptance that amyotrophic lateral sclerosis (ALS), classically considered a neurodegenerative disease affecting almost exclusively motor neurons, is syndromic with both clinical and biological heterogeneity. This is most evident in its association with a broad range of neuropsychological, behavioral, speech and language deficits [collectively termed ALS frontotemporal spectrum disorder (ALS-FTSD)]. Although the most consistent pathology of ALS and ALS-FTSD is a disturbance in TAR DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein (tau) metabolism can also be observed in ALS-FTSD, most prominently as pathological phosphorylation at Thr175 (pThr175tau). pThr175 has been shown to promote exposure of the phosphatase activating domain (PAD) in the tau N-terminus with the consequent activation of GSK3β mediated phosphorylation at Thr231 (pThr231tau) leading to pathological oligomer formation. This pathological cascade of tau phosphorylation has been observed in chronic traumatic encephalopathy with ALS (CTE-ALS) and in both in vivo and in vitro experimental paradigms, suggesting that it is of critical relevance to the pathobiology of ALS-FTSD. It is also evident that the co-existence of alterations in the metabolism of TDP-43 and tau acts synergistically in a rodent model to exacerbate the pathology of either.

scholarly journals Little Helpers or Mean Rogue—Role of Microglia in Animal Models of Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 22 (3) ◽  
pp. 993
Author(s):  
Hilal Cihankaya ◽  
Carsten Theiss ◽  
Veronika Matschke
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Disease Onset ◽  
Cellular Level ◽  
Chromosome 9 ◽  
Common Denominator ◽  
Vacuolar Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is one of the most common neurodegenerative diseases, causing degeneration of both upper and lower motor neurons in the central nervous system (CNS). ALS patients suffer from hyperreflexia, spasticity, paralysis and muscle atrophy and typically die due to respiratory failure 1–5 years after disease onset. In addition to the degeneration of motor neurons on the cellular level, ALS has been associated with neuroinflammation, such as microgliosis. Microglial activation in ALS can either be protective or degenerative to the neurons. Among others, mutations in superoxide dismutase 1 (SOD1), chromosome 9 open reading frame 72 (C9Orf72), transactive response DNA binding protein (TDP) 43 and vacuolar protein sorting-associated protein 54 (VPS54) genes have been associated with ALS. Here, we describe the dual role and functionality of microglia in four different in vivo ALS models and search for the lowest common denominator with respect to the role of microglia in the highly heterogeneous disease of ALS.

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