scholarly journals MG53 Preserves Neuromuscular Junction Integrity and Alleviates ALS Disease Progression

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1522
Author(s):  
Jianxun Yi ◽  
Ang Li ◽  
Xuejun Li ◽  
Kiho Park ◽  
Xinyu Zhou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Neuromuscular Junctions ◽  
Muscle Protein ◽  
Diaphragm Muscle ◽  
Muscle Membrane ◽  
Membrane Repair ◽  
Plasma Membrane Repair ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Increased Susceptibility

Respiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological events in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

scholarly journals MG53 preserves neuromuscular junction integrity and alleviates ALS disease progression

2021 ◽  
Author(s):  
Jianxun Yi ◽  
Ang Li ◽  
Xuejun Li ◽  
Ki Ho Park ◽  
Xinyu Zhou ◽  
...  
Keyword(s):  
Disease Progression ◽  
Neuromuscular Junctions ◽  
Muscle Protein ◽  
Diaphragm Muscle ◽  
Muscle Membrane ◽  
Membrane Repair ◽  
Plasma Membrane Repair ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Increased Susceptibility

AbstractRespiratory failure from progressive respiratory muscle weakness is the most common cause of death in amyotrophic lateral sclerosis (ALS). Defects in neuromuscular junctions (NMJs) and progressive NMJ loss occur at early stages, thus stabilizing and preserving NMJs represents a potential therapeutic strategy to slow ALS disease progression. Here we demonstrate that NMJ damage is repaired by MG53, an intrinsic muscle protein involved in plasma membrane repair. Compromised diaphragm muscle membrane repair and NMJ integrity are early pathological findings in ALS. Diaphragm muscles from ALS mouse models show increased susceptibility to injury and intracellular MG53 aggregation, which is also a hallmark of human muscle samples from ALS patients. We show that systemic administration of recombinant human MG53 protein (rhMG53) in ALS mice protects against injury to diaphragm muscle, preserves NMJ integrity, and slows ALS disease progression. As MG53 is present in circulation in rodents and humans under physiological conditions, our findings provide proof-of-concept data supporting MG53 as a potentially safe and effective therapy to mitigate ALS progression.

scholarly journals Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Massimo Tortarolo ◽  
Daniele Lo Coco ◽  
Pietro Veglianese ◽  
Antonio Vallarola ◽  
Maria Teresa Giordana ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Immune System ◽  
Disease Progression ◽  
Protective Role ◽  
Progression Rate ◽  
Neuron Death ◽  
Multisystem Disease ◽  
Als Patients ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFαis one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFαlevels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFαtoxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFαis considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFαin ALS in the light of its multisystem nature.

scholarly journals Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Thaddaeus Kwan ◽  
Mohamed Kazamel ◽  
Kristina Thoenes ◽  
Ying Si ◽  
Nan Jiang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Wnt Signaling ◽  
Disease Progression ◽  
Molecular Signature ◽  
Muscle Membrane ◽  
Denervation Atrophy ◽  
Muscle Denervation ◽  
Variable Extent ◽  
End Stage ◽  
Lateral Sclerosis

Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.

P914: Tracking disease progression in amyotrophic lateral sclerosis (ALS) patients using MUNE and macro-EMG

2014 ◽  
Vol 125 ◽  
pp. S289-S290
Author(s):  
T. Bocci ◽  
E. Giorli ◽  
M. Caleo ◽  
S. Tognazzi ◽  
F. Giannini ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Macro Emg ◽  
Als Patients ◽  
Lateral Sclerosis

scholarly journals Side of Limb-Onset Predicts Laterality of Gray Matter Loss in Amyotrophic Lateral Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Qiuli Zhang ◽  
Cuiping Mao ◽  
Jiaoting Jin ◽  
Chen Niu ◽  
Lijun Bai ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Gray Matter ◽  
Brain Atrophy ◽  
Disease Onset ◽  
Progression Rate ◽  
Imaging Evaluation ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Limb Onset

Conflicting findings have been reported regarding the lateralized brain abnormality in patients with amyotrophic lateral sclerosis (ALS). In this study, we aimed to investigate the probable lateralization of gray matter (GM) atrophy in ALS patients. We focused on the relationship between the asymmetry in decreased GM volume and the side of disease onset in patients with limb-onset. Structural imaging evaluation of normalized atrophy (SIENAX) and voxel-based morphometry (VBM) were used to assess differences in global and local brain regions in patients with heterogeneous body onset and subgroups with different side of limb-onset. We found global brain atrophy and GM losses in the frontal and parietal areas in each patient group as well as left predominant GM losses in the total cohort. The intriguing findings in subgroup analyses demonstrated that the motor cortex in the contralateral hemisphere of the initially involved limb was most affected. We also found that regional brain atrophy was related to disease progression rate. Our observations suggested that side of limb-onset can predict laterality of GM loss in ALS patients and disease progression correlates with the extent of cortical abnormality.

scholarly journals How COVID-19 pandemic changed our management strategies for amyotrophic lateral sclerosis (ALS) patients: Egyptian study

2021 ◽  
Vol 57 (1) ◽  
Author(s):  
Hebatallah R. Rashed
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
North Africa ◽  
Rating Scale ◽  
Management Strategies ◽  
Office Visits ◽  
Bulbar Onset ◽  
A Prospective Study ◽  
Als Patients ◽  
Lateral Sclerosis

Abstract Background There are several studies that have discussed the efficacy of telemedicine with amyotrophic lateral sclerosis (ALS) patients; however, this approach is still preliminary in Egypt and in North Africa. The objective of the current study is to discuss current experience with telemedicine in monitoring patients in the specialized ALS clinic in Egypt. Efficacy of Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) in monitoring disease progression remotely will be discussed. Results This is a prospective study. Forty-three ALS patients were included in this study in the period between July 1, 2020, and February 6, 2021. Fifty-three telemedicine encounters and 13 post-telemedicine office visits were available. None of the participating patients had COVID-19 infection. Eight patients showed decline in ALSFRS score. ALSFRS-R score reported during telemedicine encounters was confirmed during office visits. Three bulbar onset ALS patients had gastrostomy, and 2 bulbar onset ALS patients had Botox injection for drooling. All eight patients with declining ALSFRS-R were maintained on non-invasive ventilation (NIV) based on their symptoms. Conclusion This is the first study discussing telemedicine in the field of ALS in Egypt and North Africa. ALSFRS-R showed feasibility and reliability in detecting disease progression remotely.

scholarly journals Human diaphragm atrophy in amyotrophic lateral sclerosis is not predicted by routine respiratory measures

2019 ◽  
Vol 53 (2) ◽  
pp. 1801749 ◽  
Author(s):  
Raquel Guimarães-Costa ◽  
Thomas Similowski ◽  
Isabelle Rivals ◽  
Capucine Morélot-Panzini ◽  
Marie-Cécile Nierat ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Respiratory Muscle ◽  
Inspiratory Pressure ◽  
Diaphragm Muscle ◽  
Link Type ◽  
Slow Twitch ◽  
Diaphragm Atrophy ◽  
Als Patients ◽  
Fast Twitch ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) patients show progressive respiratory muscle weakness leading to death from respiratory failure. However, there are no data on diaphragm histological changes in ALS patients and how they correlate with routine respiratory measurements.We collected 39 diaphragm biopsies concomitantly with laparoscopic insertion of intradiaphragmatic electrodes during a randomised controlled trial evaluating early diaphragm pacing in ALS (https://clinicaltrials.gov; NCT01583088). Myofibre type, size and distribution were evaluated by immunofluorescence microscopy and correlated with spirometry, respiratory muscle strength and phrenic nerve conduction parameters. The relationship between these variables and diaphragm atrophy was assessed using multivariate regression models.All patients exhibited significant slow- and fast-twitch diaphragmatic atrophy. Vital capacity (VC), maximal inspiratory pressure, sniff nasal inspiratory pressure (SNIP) and twitch transdiaphragmatic pressure did not correlate with the severity of diaphragm atrophy. Inspiratory capacity (IC) correlated modestly with slow-twitch myofibre atrophy. Supine fall in VC correlated weakly with fast-twitch myofibre atrophy. Multivariate analysis showed that IC, SNIP and functional residual capacity were independent predictors of slow-twitch diaphragmatic atrophy, but not fast-twitch atrophy.Routine respiratory tests are poor predictors of diaphragm structural changes. Improved detection of diaphragm atrophy is essential for clinical practice and for management of trials specifically targeting diaphragm muscle function.

scholarly journals Nine Hole Peg Test and Transcranial Magnetic Stimulation: Useful to Evaluate Dexterity of the Hand and Disease Progression in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-5
Author(s):  
David Czell ◽  
Christoph Neuwirth ◽  
Markus Weber ◽  
Sabine Sartoretti-Schefer ◽  
Andreas Gutzeit ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Fine Motor ◽  
Healthy Controls ◽  
Good Tool ◽  
Resting Motor Threshold ◽  
Als Patients ◽  
Nine Hole Peg Test ◽  
Lateral Sclerosis

Objective. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with involvement of the upper and lower motor neurons. Since the loss of fine motor skills is one of the earliest signs of ALS, the hypothesis was tested if the nine hole PEG test (NHPT) and transcranial magnet stimulation (TMS) with resting-motor threshold (RMT) could be useful in monitoring disease progression. Methods. We examined 28 ALS patients and 27 age-matched healthy controls. ALS patients and healthy controls underwent the nine hole peg test (NHPT) and TMS with RMT. Measurements in patients were repeated after three and six months. Results. At baseline, the median NHPT durations were 1,4-fold longer (p<0.001), and TMS scores showed a significant 0.8-fold smaller score in ALS patients compared with healthy controls (p<0.001). The comparison of three and six months versus baseline revealed significant differences for NHPT durations and ALSFRS-R in patients, whereas TMS scores did not significantly differ in the patients. Conclusion. NHPT seems to be a good tool to evaluate dexterity of the hand and the progression of the disease in ALS patients. TMS RMT to the hand muscles seems to be poorly qualified to evaluate the dexterity of the hand function and the course of the disease.

scholarly journals Neuromuscular Junction Protection for the Potential Treatment of Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Dan Krakora ◽  
Corey Macrander ◽  
Masatoshi Suzuki
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Neuromuscular Junctions ◽  
Therapeutic Potential ◽  
Muscular Atrophy ◽  
Compensatory Mechanisms ◽  
Gene And Protein Expression ◽  
Muscle Gene ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the progressive degeneration of upper and lower motor neurons (MNs), leading to muscular atrophy and eventual respiratory failure. ALS research has primarily focused on mechanisms regarding MN cell death; however, degenerative processes in the skeletal muscle, particularly involving neuromuscular junctions (NMJs), are observed in the early stages of and throughout disease progression. According to the “dying-back” hypothesis, NMJ degeneration may not only precede, but actively cause upper and lower MN loss. The importance of NMJ pathology has relatively received little attention in ALS, possibly because compensatory mechanisms mask NMJ loss for prolonged periods. Many mechanisms explaining NMJ degeneration have been proposed such as the disruption of anterograde/retrograde axonal transport, irregular cellular metabolism, and changes in muscle gene and protein expression. Neurotrophic factors, which are known to have neuroprotective and regenerative properties, have been intensely investigated for their therapeutic potential in both the preclinical and clinical setting. Additional research should focus on the potential of preserving NMJs in order to delay or prevent disease progression

scholarly journals Circulating miR-181a-5p is a prognostic biomarker for amyotrophic lateral sclerosis

2019 ◽  
Author(s):  
Iddo Magen ◽  
Anna Coenen-Stass ◽  
Nancy Yacovzada ◽  
Julian Grosskreutz ◽  
Ching-Hua Lu ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Plasma Levels ◽  
Disease Course ◽  
Fold Reduction ◽  
System Variability ◽  
Als Patients ◽  
Clinical Phenotyping ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a relentless neurodegenerative disease affecting the motor neuron system. Variability in the rate of disease progression has limited the effectiveness of ALS clinical trials. Thus, better outcome measures are desperately needed in order to achieve therapeutic progress. Here, we investigate the potential of plasma cell-free microRNAs as biomarkers to predict ALS progression. We apply an unbiased high-throughput approach to define miRNA levels in a large cohort of ALS patients. Crucially, we conduct our analysis also on longitudinal samples reflecting disease progression, and are able to integrate detailed clinical phenotyping in our analysis. We find miR-181a-5p levels to be stable throughout the disease course and demonstrate that high miR-181a-5p plasma levels predict shortened survival in ALS patients, with a 2.5 fold reduction in median survival for patients with high miR-181a-5p plasma levels. We replicated this finding in an independent validation cohort, where an eight-fold (×8) difference in miR-181a-5p levels between the two prognosis subgroups was robustly measurable by quantitative real time PCR. In conclusion, miR-181a-5p plasma levels can predict disease course in ALS, identifying it as a novel biomarker for patient stratification with the potential to greatly enhance the effectiveness of clinical trials.One Sentence Summaryhigher plasma miR-181a-5p levels increase mortality risk in ALS patients.

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