scholarly journals The Link between Oxidative Stress, Redox Status, Bioenergetics and Mitochondria in the Pathophysiology of ALS

2021 ◽  
Vol 22 (12) ◽  
pp. 6352
Author(s):  
Elena Obrador ◽  
Rosario Salvador-Palmer ◽  
Rafael López-Blanch ◽  
Ali Jihad-Jebbar ◽  
Soraya L. Vallés ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Disease Progression ◽  
Motor Neurons ◽  
Energy Production ◽  
Redox Status ◽  
Model Systems ◽  
Pathophysiological Mechanism ◽  
Therapeutic Approaches ◽  
Survival Capacity ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor system. It is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and paralysis. ALS is incurable and has a bleak prognosis, with median survival of 3–5 years after the initial symptomatology. In ALS, motor neurons gradually degenerate and die. Many features of mitochondrial dysfunction are manifested in neurodegenerative diseases, including ALS. Mitochondria have shown to be an early target in ALS pathophysiology and contribute to disease progression. Disruption of their axonal transport, excessive generation of reactive oxygen species, disruption of the mitochondrial structure, dynamics, mitophagy, energy production, calcium buffering and apoptotic triggering have all been directly involved in disease pathogenesis and extensively reported in ALS patients and animal model systems. Alterations in energy production by motor neurons, which severely limit their survival capacity, are tightly linked to the redox status and mitochondria. The present review focuses on this link. Placing oxidative stress as a main pathophysiological mechanism, the molecular interactions and metabolic flows involved are analyzed. This leads to discussing potential therapeutic approaches targeting mitochondrial biology to slow disease progression.

scholarly journals A Study of Gene Expression Changes in Human Spinal and Oculomotor Neurons; Identifying Potential Links to Sporadic ALS

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 448
Author(s):  
Aayan N. Patel ◽  
Dennis Mathew
Keyword(s):  
Gene Expression ◽  
Disease Progression ◽  
Motor Neurons ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Tissue Samples ◽  
Disease Symptoms ◽  
Sporadic Als ◽  
Oculomotor Neurons ◽  
Als Patients

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease that causes compromised function of motor neurons and neuronal death. However, oculomotor neurons are largely spared from disease symptoms. The underlying causes for sporadic ALS as well as for the resistance of oculomotor neurons to disease symptoms remain poorly understood. In this bioinformatic-analysis, we compared the gene expression profiles of spinal and oculomotor tissue samples from control individuals and sporadic ALS patients. We show that the genes GAD2 and GABRE (involved in GABA signaling), and CALB1 (involved in intracellular Ca2+ ion buffering) are downregulated in the spinal tissues of ALS patients, but their endogenous levels are higher in oculomotor tissues relative to the spinal tissues. Our results suggest that the downregulation of these genes and processes in spinal tissues are related to sporadic ALS disease progression and their upregulation in oculomotor neurons confer upon them resistance to ALS symptoms. These results build upon prevailing models of excitotoxicity that are relevant to sporadic ALS disease progression and point out unique opportunities for better understanding the progression of neurodegenerative properties associated with sporadic ALS.

scholarly journals A cell-based platform for oxidative stress monitoring in motor neurons using genetically encoded biosensors of H2O2

2021 ◽  
Author(s):  
Elizaveta I. Ustyantseva ◽  
Suren M. Zakian ◽  
Sergey P. Medvedev
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Motor Neurons ◽  
Model Systems ◽  
Patient Specific ◽  
Ipsc Line ◽  
Stress Monitoring ◽  
A Cell ◽  
Lateral Sclerosis

ABSTRACTBackgroundOxidative stress plays an important role in the development of neurodegenerative diseases: it either can be the initiator or part of a pathological cascade leading to the neuron’s death. Although a lot of methods are known for oxidative stress study, most of them operate on non-native cellular substrates or interfere with the cell functioning. Genetically encoded (GE) biosensors of oxidative stress demonstrated their general functionality and overall safety in various live systems. However, there is still insufficient data regarding their use for research of disease-related phenotypes in relevant model systems, such as human cells.MethodsWe applied CRISPR/Cas9 genome editing to introduce mutations (c.272A>C and c.382G>C) in the associated with amyotrophic lateral sclerosis SOD1 gene of induced pluripotent stem cells (iPSC) obtained from a healthy individual. Using CRISPR/Cas9, we modified these mutant iPSC lines, as well as the parental iPSC line, and a patient-specific SOD1D91A/D91A iPSC line with ratiometric GE biosensors of cytoplasmic (Cyto-roGFP2-Orp1) and mitochondrial (Mito-roGFP2-Orp1) H2O2. The biosensors sequences along with a specific transactivator for doxycycline-controllable expression were inserted in the “safe harbor” AAVS1 (adeno-associated virus site 1) locus. We differentiated these transgenic iPSCs into motor neurons and investigated the functionality of the biosensors in such a system. We measured relative oxidation in the cultured motor neurons and its dependence on culture conditions, age, and genotype, as well as kinetics of H2O2 elimination in real-time.ResultsWe developed a cell-based platform consisting of isogenic iPSC lines with different genotypes associated with amyotrophic lateral sclerosis. The iPSC lines were modified with GE biosensors of cytoplasmic and mitochondrial H2O2. We provide proof-of-principle data showing that this approach may be suitable for monitoring oxidative stress in cell models of various neurodegenerative diseases as the biosensors reflect the redox state of neurons.ConclusionWe found that the GE biosensors inserted in the AAVS1 locus remain functional in motor neurons and reflect pathological features of mutant motor neurons, although the readout largely depends on the severity of the mutation.

scholarly journals ALS monocyte-derived microglia reveal cytoplasmic TDP-43 accumulation, DNA damage, and cell-specific impairment of phagocytosis associated with disease progression

2020 ◽  
Author(s):  
Hazel Quek ◽  
Carla Cuní-López ◽  
Romal Stewart ◽  
Tiziana Colletti ◽  
Antonietta Notaro ◽  
...  
Keyword(s):  
Dna Damage ◽  
Disease Progression ◽  
Motor Neurons ◽  
Clinical Pathology ◽  
Cost Effective ◽  
Model System ◽  
Rapid Progression ◽  
Depth Analysis ◽  
Progression Of Disease ◽  
Als Patients

AbstractAimsAmyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Neuroinflammation mediated by microglial activation is evident in post-mortem brain tissues, and in brain imaging of patients with ALS. However, the exact role of microglia in ALS remains to be elucidated partly due to the lack of an accurate microglial model system that is able to recapitulate the clinical pathology of ALS. Moreover, direct sampling of microglia from patients with ALS is not feasible, further limiting the study of microglial function in ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia (MDMi) that are capable of expressing molecular markers, and functional characteristics similar to resident human brain microglia. Importantly, MDMi can be routinely and reproducibly generated from ALS patient blood, and reveal patient heterogeneity associated with age, sex and disease subgroup.MethodsMDMi were successfully established from all 30 ALS patients, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected heathy controls (HC).ResultsOur ALS MDMi model recapitulated canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive pathological inclusions. We further observed significantly impaired phagocytosis, altered cytokine expression and microglial morphology, as well as elevated DNA damage in ALS compared to HC MDMi. Abnormal phagocytosis was observed in all ALS cases, and was correlated to the progression of disease. Moreover, in-depth analysis of individual microglia revealed cell-specific variation in phagocytic function that was significantly altered, and exacerbated in rapid disease progression.ConclusionsOur approach enabled us to generate ALS patient microglia from peripheral blood samples using a rapid, robust, cost-effective, and reproducible protocol. We have shown that ALS monocyte-derived microglia have significantly altered functional behaviour compared to age-matched HCs, with a major deficit in phagocytic activity. This is also the first demonstration of abnormal TDP-43 localisation in microglia grown from ALS patients. Overall, this approach is highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents. Additionally, this model system can be used as a basis for personalised therapeutic treatment for ALS, as well as other neurodegenerative diseases.

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 Oxidant–Antioxidant Status in Canine Multicentric Lymphoma and Primary Cutaneous Mastocytoma

Processes ◽  
2020 ◽  
Vol 8 (7) ◽  
pp. 802 ◽  
Author(s):  
Andrea Cucchi ◽  
Roberto Ramoni ◽  
Giuseppina Basini ◽  
Simona Bussolati ◽  
Fausto Quintavalla
Keyword(s):  
Oxidative Stress ◽  
Redox Status ◽  
Stress Index ◽  
Therapeutic Approaches ◽  
Antioxidant Power ◽  
New Therapeutic Approaches ◽  
Oncologic Patients ◽  
Ferric Reducing Antioxidant Power ◽  
Enzyme Superoxide Dismutase ◽  
Multicentric Lymphoma

Oxidative stress is a prominent event in several acute and chronic diseases including neoplasia. Although its direct involvement in carcinogenesis still remains to be clearly defined, a deeper knowledge of oxidative stress in oncologic patients could help to monitor their clinical outcome and to develop new therapeutic approaches. Therefore, the present study was undertaken to explore redox status in blood of neoplastic dogs affected either by multicentric lymphoma or by primary cutaneous mastocytoma. Superoxide anion (O2 •−), nitric oxide (NO) and hydroperoxides (ROOH) were measured. Detoxifying enzyme superoxide dismutase (SOD) and total non-enzymatic antioxidant capacity (ferric reducing-antioxidant power (FRAP)) were assessed. The oxidative stress index (OSi) both for enzymatic (OSiE) and non-enzymatic (OSiNE) scavengers were evaluated. Both pathologies, showed a reduced NO generation, while O2 •− levels were decreased only in mastocytoma. The oxidative stress indexes showed a significant decrease in mastocytoma patients, only for OSiE.

scholarly journals Adipsin, MIP-1b, and IL-8 as CSF Biomarker Panels for ALS Diagnosis

2018 ◽  
Vol 2018 ◽  
pp. 1-5 ◽  
Author(s):  
Maria Teresa Gonzalez-Garza ◽  
Hector Ramon Martinez ◽  
Delia E. Cruz-Vega ◽  
Martin Hernandez-Torre ◽  
Jorge E. Moreno-Cuevas
Keyword(s):  
Motor Neurons ◽  
Rating Scales ◽  
Neurodegenerative Disorder ◽  
Panel Analysis ◽  
Therapeutic Approaches ◽  
Reliable Diagnosis ◽  
Als Patients ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is an aggressive neurodegenerative disorder that selectively attacks motor neurons in the brain and spinal cord. Despite important advances in the knowledge of the etiology and progression of the disease, there are still no solid grounds in which a clinician could make an early objective and reliable diagnosis from which patients could benefit. Diagnosis is difficult and basically made by clinical rating scales (ALSRs and El Escorial). The possible finding of biomarkers to aid in the early diagnosis and rate of disease progression could serve for future innovative therapeutic approaches. Recently, it has been suggested that ALS has an important immune component that could represent either the cause or the consequence of the disease. In this report, we analyzed 19 different cytokines and growth factors in the cerebrospinal fluid of 77 ALS patients and 13 controls by decision tree and PanelomiX program. Results showed an increase of Adipsin, MIP-1b, and IL-6, associated with a decrease of IL-8 thresholds, related with ALS patients. This biomarker panel analysis could represent an important aid for diagnosis of ALS alongside the clinical and neurophysiological criteria.

Oxidative Stress and Atherosclerosis: Its Relationship to Growth Factors, Thrombus Formation and Therapeutic Approaches

1999 ◽  
Vol 82 (S 01) ◽  
pp. 32-37 ◽  
Author(s):  
Karlheinz Peter ◽  
Wolfgang Kübler ◽  
Johannes Ruef ◽  
Thomas K. Nordt ◽  
Marschall S. Runge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Growth Factors ◽  
Vessel Wall ◽  
Inflammatory Responses ◽  
Plaque Rupture ◽  
Thrombus Formation ◽  
Vascular Lesion ◽  
Coagulation System ◽  
Therapeutic Approaches ◽  
Causative Relationship

SummaryThe initiating event of atherogenesis is thought to be an injury to the vessel wall resulting in endothelial dysfunction. This is followed by key features of atherosclerotic plaque formation such as inflammatory responses, cell proliferation and remodeling of the vasculature, finally leading to vascular lesion formation, plaque rupture, thrombosis and tissue infarction. A causative relationship exists between these events and oxidative stress in the vessel wall. Besides leukocytes, vascular cells are a potent source of oxygen-derived free radicals. Oxidants exert mitogenic effects that are partially mediated through generation of growth factors. Mitogens, on the other hand, are potent stimulators of oxidant generation, indicating a putative self-perpetuating mechanism of atherogenesis. Oxidants influence the balance of the coagulation system towards platelet aggregation and thrombus formation. Therapeutic approaches by means of antioxidants are promising in both experimental and clinical designs. However, additional clinical trials are necessary to assess the role of antioxidants in cardiovascular disease.

Riluzole Exhibits No Therapeutic Efficacy on a Transgenic Rat model of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 17 (3) ◽  
pp. 275-285 ◽  
Author(s):  
Si Chen ◽  
Qiao Liao ◽  
Ke Lu ◽  
Jinxia Zhou ◽  
Cao Huang ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rat Model ◽  
Microglial Activation ◽  
Transgenic Rat ◽  
Intragastric Administration ◽  
Behavioral Deficits ◽  
Als Patients ◽  
Lateral Sclerosis ◽  
Transgenic Rat Model

Background: Amyotrophic lateral sclerosis (ALS) is a neurological disorder clinically characterized by motor system dysfunction, with intraneuronal accumulation of the TAR DNAbinding protein 43 (TDP-43) being a pathological hallmark. Riluzole is a primarily prescribed medicine for ALS patients, while its therapeutical efficacy appears limited. TDP-43 transgenic mice are existing animal models for mechanistic/translational research into ALS. Methods: We developed a transgenic rat model of ALS expressing a mutant human TDP-43 transgene (TDP-43M337V) and evaluated the therapeutic effect of Riluzole on this model. Relative to control, rats with TDP-43M337V expression promoted by the neurofilament heavy subunit (NEF) gene or specifically in motor neurons promoted by the choline acetyltransferase (ChAT) gene showed progressive worsening of mobility and grip strength, along with loss of motor neurons, microglial activation, and intraneuronal accumulation of TDP-43 and ubiquitin aggregations in the spinal cord. Results: Compared to vehicle control, intragastric administration of Riluzole (30 mg/kg/d) did not mitigate the behavioral deficits nor alter the neuropathologies in the transgenics. Conclusion: These findings indicate that transgenic rats recapitulate the basic neurological and neuropathological characteristics of human ALS, while Riluzole treatment can not halt the development of the behavioral and histopathological phenotypes in this new transgenic rodent model of ALS.

scholarly journals Interleukin-17 and Th17 Lymphocytes Directly Impair Motoneuron Survival of Wildtype and FUS-ALS Mutant Human iPSCs

2021 ◽  
Vol 22 (15) ◽  
pp. 8042
Author(s):  
Mengmeng Jin ◽  
Katja Akgün ◽  
Tjalf Ziemssen ◽  
Markus Kipp ◽  
Rene Günther ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Th17 Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Positive Control ◽  
Interleukin 17 ◽  
Fused In Sarcoma ◽  
Th17 Lymphocytes ◽  
Human Ipscs ◽  
Als Patients

Amyotrophic lateral sclerosis (ALS) is a progressive disease leading to the degeneration of motor neurons (MNs). Neuroinflammation is involved in the pathogenesis of ALS; however, interactions of specific immune cell types and MNs are not well studied. We recently found a shift toward T helper (Th)1/Th17 cell-mediated, pro-inflammatory immune responses in the peripheral immune system of ALS patients, which positively correlated with disease severity and progression. Whether Th17 cells or their central mediator, Interleukin-17 (IL-17), directly affects human motor neuron survival is currently unknown. Here, we evaluated the contribution of Th17 cells and IL-17 on MN degeneration using the co-culture of iPSC-derived MNs of fused in sarcoma (FUS)-ALS patients and isogenic controls with Th17 lymphocytes derived from ALS patients, healthy controls, and multiple sclerosis (MS) patients (positive control). Only Th17 cells from MS patients induced severe MN degeneration in FUS-ALS as well as in wildtype MNs. Their main effector, IL-17A, yielded in a dose-dependent decline of the viability and neurite length of MNs. Surprisingly, IL-17F did not influence MNs. Importantly, neutralizing IL-17A and anti-IL-17 receptor A treatment reverted all effects of IL-17A. Our results offer compelling evidence that Th17 cells and IL-17A do directly contribute to MN degeneration.

scholarly journals Dexamethasone increased the survival rate in Plasmodium berghei-infected mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Danilo Reymão Moreira ◽  
Ana Carolina Musa Gonçalves Uberti ◽  
Antonio Rafael Quadros Gomes ◽  
Michelli Erica Souza Ferreira ◽  
Aline da Silva Barbosa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Survival Rate ◽  
Plasmodium Berghei ◽  
Redox Status ◽  
No Synthase ◽  
Ischemia And Reperfusion ◽  
Inos Inhibition ◽  
The Brain ◽  
Plasmodial Infection ◽  
Stimulation Of

AbstractThe present study aimed to evaluate the effects of dexamethasone on the redox status, parasitemia evolution, and survival rate of Plasmodium berghei-infected mice. Two-hundred and twenty-five mice were infected with Plasmodium berghei and subjected to stimulation or inhibition of NO synthesis. The stimulation of NO synthesis was performed through the administration of L-arginine, while its inhibition was made by the administration of dexamethasone. Inducible NO synthase (iNOS) inhibition by dexamethasone promoted an increase in the survival rate of P. berghei-infected mice, and the data suggested the participation of oxidative stress in the brain as a result of plasmodial infection, as well as the inhibition of brain NO synthesis, which promoted the survival rate of almost 90% of the animals until the 15th day of infection, with possible direct interference of ischemia and reperfusion syndrome, as seen by increased levels of uric acid. Inhibition of brain iNOS by dexamethasone caused a decrease in parasitemia and increased the survival rate of infected animals, suggesting that NO synthesis may stimulate a series of compensatory redox effects that, if overstimulated, may be responsible for the onset of severe forms of malaria.

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