Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis

2002 ◽  
Vol 52 (4) ◽  
pp. 448-457 ◽  
Author(s):  
Roy G. Cutler ◽  
Ward A. Pedersen ◽  
Simonetta Camandola ◽  
Jeffrey D. Rothstein ◽  
Mark P. Mattson
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cholesterol Esters ◽  
Lateral Sclerosis

scholarly journals RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

2015 ◽  
Vol 35 (14) ◽  
pp. 2385-2399 ◽  
Author(s):  
Nadine Bakkar ◽  
Arianna Kousari ◽  
Tina Kovalik ◽  
Yang Li ◽  
Robert Bowser
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Antioxidant Response ◽  
Cytoplasmic Inclusions ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulatedin vitroin motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.

scholarly journals Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 8 (5) ◽  
pp. 729 ◽  
Author(s):  
Matteo Bordoni ◽  
Orietta Pansarasa ◽  
Michela Dell’Orco ◽  
Valeria Crippa ◽  
Stella Gagliardi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Oxidative Damage ◽  
Motor Neurons ◽  
Mononuclear Cells ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Peripheral Blood Mononuclear ◽  
High Level ◽  
Lateral Sclerosis

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target.

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 Oxidative Stress in Amyotrophic Lateral Sclerosis: Pathophysiology and Opportunities for Pharmacological Intervention

2020 ◽  
Vol 2020 ◽  
pp. 1-29
Author(s):  
Teresa Cunha-Oliveira ◽  
Liliana Montezinho ◽  
Catarina Mendes ◽  
Omidreza Firuzi ◽  
Luciano Saso ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Therapeutic Benefit ◽  
Pharmacological Intervention ◽  
Antioxidant Compounds ◽  
Pathological Feature ◽  
Beneficial Effects ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.

scholarly journals Dysregulations of Expression of Genes of the Ubiquitin/SUMO Pathways in an In Vitro Model of Amyotrophic Lateral Sclerosis Combining Oxidative Stress and SOD1 Gene Mutation

2021 ◽  
Vol 22 (4) ◽  
pp. 1796
Author(s):  
Audrey Dangoumau ◽  
Sylviane Marouillat ◽  
Roxane Coelho ◽  
François Wurmser ◽  
Céline Brulard ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Genetic Alterations ◽  
Sod1 Gene ◽  
Altered Expression ◽  
Expression Of Genes ◽  
Vitro Model ◽  
Lateral Sclerosis

Protein aggregates in affected motor neurons are a hallmark of amyotrophic lateral sclerosis (ALS), but the molecular pathways leading to their formation remain incompletely understood. Oxidative stress associated with age, the major risk factor in ALS, contributes to this neurodegeneration in ALS. We show that several genes coding for enzymes of the ubiquitin and small ubiquitin-related modifier (SUMO) pathways exhibit altered expression in motor neuronal cells exposed to oxidative stress, such as the CCNF gene mutated in ALS patients. Eleven of these genes were further studied in conditions combining oxidative stress and the expression of an ALS related mutant of the superoxide dismutase 1 (SOD1) gene. We observed a combined effect of these two environmental and genetic factors on the expression of genes, such as Uhrf2, Rbx1, Kdm2b, Ube2d2, Xaf1, and Senp1. Overall, we identified dysregulations in the expression of enzymes of the ubiquitin and SUMO pathways that may be of interest to better understand the pathophysiology of ALS and to protect motor neurons from oxidative stress and genetic alterations.

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 Oxidative Stress as a Therapeutic Target in Amyotrophic Lateral Sclerosis: Opportunities and Limitations

Diagnostics ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1546
Author(s):  
Hee Ra Park ◽  
Eun Jin Yang
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Animal Models ◽  
Motor Neurons ◽  
Neuronal Degeneration ◽  
Upper Motor Neurons ◽  
Potential Therapeutics ◽  
Lateral Sclerosis ◽  
Oxidative Agents

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) and Lou Gehrig’s disease, is characterized by a loss of the lower motor neurons in the spinal cord and the upper motor neurons in the cerebral cortex. Due to the complex and multifactorial nature of the various risk factors and mechanisms that are related to motor neuronal degeneration, the pathological mechanisms of ALS are not fully understood. Oxidative stress is one of the known causes of ALS pathogenesis. This has been observed in patients as well as in cellular and animal models, and is known to induce mitochondrial dysfunction and the loss of motor neurons. Numerous therapeutic agents have been developed to inhibit oxidative stress and neuroinflammation. In this review, we describe the role of oxidative stress in ALS pathogenesis, and discuss several anti-inflammatory and anti-oxidative agents as potential therapeutics for ALS. Although oxidative stress and antioxidant fields are meaningful approaches to delay disease progression and prolong the survival in ALS, it is necessary to investigate various animal models or humans with different subtypes of sporadic and familial ALS.

scholarly journals An Intercellular Flow of Glutathione Regulated by Interleukin 6 Links Astrocytes and the Liver in the Pathophysiology of Amyotrophic Lateral Sclerosis

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 2007
Author(s):  
Rafael López-Blanch ◽  
Rosario Salvador-Palmer ◽  
José M. Estrela ◽  
Elena Obrador
Keyword(s):  
Oxidative Stress ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Interleukin 6 ◽  
Blood Circulation ◽  
Physiological Conditions ◽  
Major Mechanism ◽  
Neuron Damage ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Oxidative stress has been proposed as a major mechanism of damage to motor neurons associated with the progression of amyotrophic lateral sclerosis (ALS). Astrocytes are the most numerous glial cells in the central nervous system and, under physiological conditions, protect neurons from oxidative damage. However, it is uncertain how their reactive phenotype may affect motor neurons during ALS progression. In two different ALS mouse models (SOD1G93A and FUS-R521C), we found that increased levels of proinflammatory interleukin 6 facilitate glutathione (GSH) release from the liver to blood circulation, which can reach the astrocytes and be channeled towards motor neurons as a mechanism of antioxidant protection. Nevertheless, although ALS progression is associated with an increase in GSH efflux from astrocytes, generation of reactive oxygen species also increases, suggesting that as the disease progresses, astrocyte-derived oxidative stress could be key to motor-neuron damage.

Exploring molecular approaches in Amyotrophic lateral sclerosis: Drug targets from clinical and pre-clinical findings

2020 ◽  
Vol 13 ◽  
Author(s):  
Mamtaj Alam ◽  
Rajeshwar Kumar Yadav ◽  
Elizabeth Minj ◽  
Aarti Tiwari ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Drug Targets ◽  
Therapeutic Index ◽  
Experimental Models ◽  
Clinical Findings ◽  
Adenyl Cyclase ◽  
Molecular Approaches ◽  
Pharmacologically Active ◽  
Lateral Sclerosis

: Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) characterised by the death of upper and lower motor neurons (corticospinal tract) in the motor cortex, basal ganglia, brain stem, and spinal cord. The patient experiences the sign and symptoms between 55 to 75 years of age included impaired motor movement, difficulty in speaking and swallowing, grip loss, muscle atrophy, spasticity and sometimes associated with memory and cognitive impairments. Median survival is 3 to 5 years after diagnosis and 5 to 10% beyond 10 years of age. The limited intervention of pharmacologically active compounds that are used clinically is majorly associated with the narrow therapeutic index. Pre-clinically established experimental models where neurotoxin methyl mercury mimics the ALS like behavioural and neurochemical alterations in rodents associated with neuronal mitochondrial dysfunctions and downregulation of adenyl cyclase mediated cAMP/CREB is the main pathological hallmark for the progression of ALS in central as well in the peripheral nervous system. Despite the considerable investigation into neuroprotection, it still constrains treatment choices to strong care and organization of ALS complications. Therefore, current review specially targeted in the investigation of clinical and pre-clinical features available for ALS to understand the pathogenic mechanisms and to explore the pharmacological interventions associated with up-regulation of intracellular adenyl cyclase/cAMP/CREB and mitochondrial-ETC coenzyme-Q10 activation as a future drug target in the amelioration of ALS mediated motor neuronal dysfunctions.

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