scholarly journals Insights into the mechanisms of copper dyshomeostasis in amyotrophic lateral sclerosis

2017 ◽  
Vol 19 ◽  
Author(s):  
Francisco J Gil-Bea ◽  
Garazi Aldanondo ◽  
Haizpea Lasa-Fernández ◽  
Adolfo López de Munain ◽  
Ainara Vallejo-Illarramendi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Prion Diseases ◽  
Disease Onset ◽  
Copper Homeostasis ◽  
The Central Nervous System ◽  
Novel Approaches ◽  
Copper Dyshomeostasis ◽  
Copper Delivery ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a severe neuromuscular disease characterised by a progressive loss of motor neurons that usually results in paralysis and death within 2 to 5 years after disease onset. The pathophysiological mechanisms involved in ALS remain largely unknown and to date there is no effective treatment for this disease. Here, we review clinical and experimental evidence suggesting that dysregulation of copper homeostasis in the central nervous system is a crucial underlying event in motor neuron degeneration and ALS pathophysiology. We also review and discuss novel approaches seeking to target copper delivery to treat ALS. These novel approaches may be clinically relevant not only for ALS but also for other neurological disorders with abnormal copper homeostasis, such as Parkinson's, Huntington's and Prion diseases.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

scholarly journals LanCL1 promotes motor neuron survival and extends the lifespan of amyotrophic lateral sclerosis mice

2019 ◽  
Vol 27 (4) ◽  
pp. 1369-1382 ◽  
Author(s):  
Honglin Tan ◽  
Mina Chen ◽  
Dejiang Pang ◽  
Xiaoqiang Xia ◽  
Chongyangzi Du ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neuronal Survival ◽  
Disease Onset ◽  
Alternative Mechanism ◽  
Specific Expression ◽  
Motor Neuron Survival ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons. Improving neuronal survival in ALS remains a significant challenge. Previously, we identified Lanthionine synthetase C-like protein 1 (LanCL1) as a neuronal antioxidant defense gene, the genetic deletion of which causes apoptotic neurodegeneration in the brain. Here, we report in vivo data using the transgenic SOD1G93A mouse model of ALS indicating that CNS-specific expression of LanCL1 transgene extends lifespan, delays disease onset, decelerates symptomatic progression, and improves motor performance of SOD1G93A mice. Conversely, CNS-specific deletion of LanCL1 leads to neurodegenerative phenotypes, including motor neuron loss, neuroinflammation, and oxidative damage. Analysis reveals that LanCL1 is a positive regulator of AKT activity, and LanCL1 overexpression restores the impaired AKT activity in ALS model mice. These findings indicate that LanCL1 regulates neuronal survival through an alternative mechanism, and suggest a new therapeutic target in ALS.

scholarly journals Pulmonary function in patients with Amyotrophic Lateral Sclerosis at disease onset

2015 ◽  
Vol 77 (3-4) ◽  
Author(s):  
B. Chandrasoma ◽  
D. Balfe ◽  
T. Naik ◽  
A. Elsayegh ◽  
M. Lewis ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Pulmonary Function ◽  
Muscle Weakness ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Pulmonary Function Tests ◽  
Disease Onset ◽  
Group Versus ◽  
Combination Methods ◽  
Lateral Sclerosis

Background. Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting both the upper and lower motor neurons. Deteriorating pulmonary function as a reflection of progressive respiratory muscle weakness is a common feature, accounting for the majority of deaths. The aim of the study was to describe a trend in initial pulmonary function tests (PFT) of Amyotrophic Lateral Sclerosis (ALS) patients, in addition, differentiating between the types of disease onset, bulbar, limb muscle, and a combination. Methods. Initial PFT were gathered from 32 consecutive patients in our clinic with the diagnosis of ALS, they were categorized by the type of disease onset. Values obtained were referenced to the 95% confidence limits for normality. Results. There was evidence of significant reductions in both the FEV1 (64.7% predicted) and FVC (61.2%), with preservation of the FEV1/FVC (81.7%). The MVV was significantly reduced(43%). Total lung capacity was 93.2%, the residual volumes was increased at 145.7%. Subgroup analysis failed to show significant differences between types of disease onset. In the bulbar onset group (versus the limb group) there was a trend for the MVV to be further reduced (p=0.15) and the RV to be higher (157.4% versus 135.9%, P=0.24). Conclusions. ALS is a devastating disease that invariably leads to respiratory failure. Abnormal spirometric variables such as the FVC and MVV, likely reflect inspiratory muscle weakness and increased RV likely reflect expiratory muscle weakness. The type of disease onset did not result in a different pattern of PFT abnormalities.

scholarly journals Dissociation of disease onset, progression and sex differences from androgen receptor levels in a mouse model of amyotrophic lateral sclerosis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Doris Tomas ◽  
Victoria M. McLeod ◽  
Mathew D. F. Chiam ◽  
Nayomi Wanniarachchillage ◽  
Wah C. Boon ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Sex Differences ◽  
Androgen Receptor ◽  
Mouse Model ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Disease Onset ◽  
Disease Course ◽  
Male Mice ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder caused by loss of motor neurons. ALS incidence is skewed towards males with typically earlier age of onset and limb site of onset. The androgen receptor (AR) is the major mediator of androgen effects in the body and is present extensively throughout the central nervous system, including motor neurons. Mutations in the AR gene lead to selective lower motor neuron degeneration in male spinal bulbar muscular atrophy (SBMA) patients, emphasising the importance of AR in maintaining motor neuron health and survival. To evaluate a potential role of AR in onset and progression of ALS, we generated SOD1G93A mice with either neural AR deletion or global human AR overexpression. Using a Cre-LoxP conditional gene knockout strategy, we report that neural deletion of AR has minimal impact on the disease course in SOD1G93A male mice. This outcome was potentially confounded by the metabolically disrupted Nestin-Cre phenotype, which likely conferred the profound lifespan extension observed in the SOD1G93A double transgenic male mice. In addition, overexpression of human AR produced no benefit to disease onset and progression in SOD1G93A mice. In conclusion, the disease course of SOD1G93A mice is independent of AR expression levels, implicating other mechanisms involved in mediating the sex differences in ALS. Our findings using Nestin-Cre mice, which show an inherent metabolic phenotype, led us to hypothesise that targeting hypermetabolism associated with ALS may be a more potent modulator of disease, than AR in this mouse model.

scholarly journals Kinematic gait analysis of patients with amyotrophic lateral sclerosis: presentation of three cases / Análise cinemática da marcha em pacientes com esclerose lateral amiotrófica: apresentação de três casos

2017 ◽  
Vol 7 (4) ◽  
pp. 15-19
Author(s):  
Fernanda Cechetti ◽  
Gabriela Farias ◽  
Marina Sangali ◽  
Thiago de Marchi ◽  
Aline de Souza Pagnussat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cross Sectional ◽  
Gait Kinematics ◽  
Temporal Variables ◽  
The Central Nervous System ◽  
Degenerative Disorder ◽  
Hip Flexion ◽  
Kinematic Gait Analysis ◽  
Lateral Sclerosis

Amyotrophic Lateral Sclerosis is a degenerative disorder of the central nervous system involving motor neurons, which directly affect the gait of a person. The aim of this study was to analyze the gait kinematics of patients affected by this pathology in different stages. A descriptive cross-sectional research was designed with three subjects who were classified in stages I, II and III proposed by Sinaki & Mulder. Regarding the spatial-temporal variables, it was observed that the more the stage of the pathology progresses, the further the values get from normality. In the angular kinematic parameters, there was a greater hip flexion to achieve ambulation, together with a decrease in the extension in the three joints studied. The results showed that the data from the subjects presenting amyotrophic lateral sclerosis differ from normal at all stages and the losses caused by the disease have direct influence on gait kinematics mainly with the progress of the disease when the overall symptoms become more incapacitating.Keywords: Amyotrophic lateral sclerosis; Gait; KinematicsA Esclerose Lateral Amiotrófica é um distúrbio degenerativo do sistema nervoso central envolvendo neurônios motores que afetam diretamente a marcha. O objetivo deste estudo foi analisar a cinemática da marcha de indivíduos afetados por esta patologia, em diferentes estágios. Trata-se de uma pesquisa descritiva transversal em três sujeitos classificados entre os estágios I, II e III propostos por Sinaki e Mulder. Em relação às variáveis espaço-temporais, observa-se que conforme o estágio da patologia avança, mais os valores se distanciam da normalidade. Nos parâmetros cinemáticos angulares, observa-se maior flexão de quadril para conseguir deambular, somada a uma diminuição na extensão nas três articulações estudadas. Os resultados demostram que os dados destes indivíduos diferem da normalidade em todos os estágios e as perdas causadas pela doença têm influência direta na cinemática da marcha, principalmente com o progresso da doença, quando os sintomas gerais se tornam mais incapacitantes.Palavras-Chave: Esclerose lateral amiotrófica; Marcha; Cinemática

scholarly journals Biomolecular Modifications Linked to Oxidative Stress in Amyotrophic Lateral Sclerosis: Determining Promising Biomarkers Related to Oxidative Stress

Processes ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1667
Author(s):  
Takashi Hosaka ◽  
Hiroshi Tsuji ◽  
Akira Tamaoka
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Extracellular Proteins ◽  
Clinical Effects ◽  
Oxidation Reactions ◽  
Incurable Disease ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
Lateral Sclerosis

Reduction–oxidation reactions are essential to cellular homeostasis. Oxidative stress transcends physiological antioxidative system damage to biomolecules, including nucleic acids and proteins, and modifies their structures. Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. The cells present in the central nervous system, including motor neurons, are vulnerable to oxidative stress. Neurodegeneration has been demonstrated to be caused by oxidative biomolecular modifications. Oxidative stress has been suggested to be involved in the pathogenesis of ALS. Recent progress in research on the underlying mechanisms of oxidative stress in ALS has led to the development of disease-modifying therapies, including edaravone. However, the clinical effects of edaravone remain limited, and ALS is a heretofore incurable disease. The reason for the lack of reliable biomarkers and the precise underlying mechanisms between oxidative stress and ALS remain unclear. As extracellular proteins and RNAs present in body fluids and represent intracellular pathological neurodegenerative processes, extracellular proteins and/or RNAs are predicted to promise diagnosis, prediction of disease course, and therapeutic biomarkers for ALS. Therefore, we aimed to elucidate the underlying mechanisms between oxidative stress and ALS, and promising biomarkers indicating the mechanism to determine whether therapy targeting oxidative stress can be fundamental for ALS.

scholarly journals A review: Management of motor neuron diseases

2022 ◽  
Vol 7 (4) ◽  
pp. 292-294
Author(s):  
Aarti Chopra ◽  
Ravi Kumar ◽  
Girendra Kumar Gautam
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Age At Onset ◽  
Motor Neuron Diseases ◽  
Progressive Degeneration ◽  
Review Management ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Motor neuron diseases are a group of chronic sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons. These might affect the upper motor neurons, lower motor neurons, or both. The prognosis of the motor neuron disease depends upon the age at onset and the area of the central nervous system affected. Amyotrophic lateral sclerosis (ALS) has been documented to be fatal within three years of onset. This activity focuses on amyotrophic lateral sclerosis as the prototype of MND, which affects both the upper and the lower motor neurons and discusses the role of inter-professional team in the differential diagnosis, evaluation, treatment, and prognostication. It also discusses various other phenotypes of MND with an emphasis on their distinguishing features in requisite detail.

scholarly journals Evaluation of drugs for treatment of prion infections of the central nervous system

2008 ◽  
Vol 89 (2) ◽  
pp. 594-597 ◽  
Author(s):  
Constanze Riemer ◽  
Michael Burwinkel ◽  
Anja Schwarz ◽  
Sandra Gültner ◽  
Simon W. F. Mok ◽  
...  
Keyword(s):  
Prion Diseases ◽  
Disease Onset ◽  
Therapeutic Benefit ◽  
High Dose ◽  
Therapeutic Approaches ◽  
Minocycline Treatment ◽  
Delay Disease Onset ◽  
The Central Nervous System ◽  
Pass Through ◽  
Lateral Sclerosis

Prion diseases are fatal and at present there are neither cures nor therapies available to delay disease onset or progression in humans. Inspired in part by therapeutic approaches in the fields of Alzheimer's disease and amyotrophic lateral sclerosis, we tested five different drugs, which are known to efficiently pass through the blood–brain barrier, in a murine prion model. Groups of intracerebrally prion-challenged mice were treated with the drugs curcumin, dapsone, ibuprofen, memantine and minocycline. Treatment with antibiotics dapsone and minocycline had no therapeutic benefit. Ibuprofen-treated mice showed severe adverse effects, which prevented assessment of therapeutic efficacy. Mice treated with low- but not high-dose curcumin and mice treated with memantine survived infections significantly longer than untreated controls (P<0.01). These results encourage further research efforts to improve the therapeutic effect of these drugs.

scholarly journals Reducing EphA4 before disease onset does not affect survival in a mouse model of Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Rué ◽  
Mieke Timmers ◽  
Annette Lenaerts ◽  
Silke Smolders ◽  
Lindsay Poppe ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Motor Neurons ◽  
Developmental Stages ◽  
Time Window ◽  
Therapeutic Potential ◽  
Disease Onset ◽  
Axonal Guidance ◽  
Tyrosine Kinase Receptor ◽  
Lateral Sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons resulting in severe neurological symptoms. Previous findings of our lab suggested that the axonal guidance tyrosine-kinase receptor EphA4 is an ALS disease-modifying gene. Reduction of EphA4 from developmental stages onwards rescued a motor neuron phenotype in zebrafish, and heterozygous deletion before birth in the SOD1G93A mouse model of ALS resulted in improved survival. Here, we aimed to gain more insights in the cell-specific role of decreasing EphA4 expression in addition to timing and amount of EphA4 reduction. To evaluate the therapeutic potential of lowering EphA4 later in life, we ubiquitously reduced EphA4 levels to 50% in SOD1G93A mice at 60 days of age, which did not modify disease parameters. Even further lowering EphA4 levels ubiquitously or in neurons, did not improve disease onset or survival. These findings suggest that lowering EphA4 as target in ALS may suffer from a complex therapeutic time window. In addition, the complexity of the Eph-ephrin signalling system may also possibly limit the therapeutic potential of such an approach in ALS. We suggest here that a specific EphA4 knockdown in adulthood may have a limited therapeutic potential for ALS.

scholarly journals Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Asako Otomo ◽  
Lei Pan ◽  
Shinji Hadano
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Ubiquitin Proteasome System ◽  
Protective Role ◽  
Motor Neuron Diseases ◽  
Ubiquitin Proteasome ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

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