scholarly journals Integrated Multi-Omic Data Analysis and Validation with Yeast Model Show Oxidative Phosphorylation Modulate Protein Aggregation in Amyotrophic Lateral Sclerosis

2021 ◽  
Author(s):  
Sai Swaroop ◽  
Akhil PS ◽  
Sai Sanwid Pradhan ◽  
Bandana Prasad ◽  
Raksha Rao ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Oxidative Phosphorylation ◽  
Complex I ◽  
Critical Role ◽  
Complex Iii ◽  
Integrative Approach ◽  
Complex Iv ◽  
Knock Out ◽  
Lateral Sclerosis ◽  
Yeast Model

Abstract Amyotrophic Lateral Sclerosis is a progressive, incurable amyloid aggregating neurodegenerative disease involving the motor neurons. Identification of potential biomarkers and therapeutic targets can assist in the better management of the disease. We used an integrative approach encompassing analysis of transcriptomic datasets of human and mice from GEO database. Our analysis of ALS patient datasets showed deregulation in Non-alcoholic fatty acid liver disease and oxidative phosphorylation. Transgenic mice datasets pertaining to SOD1, FUS and TDP-43 showed deregulation in oxidative phosphorylation and ribosome associated pathways. Commonality analysis between the human and mice datasets showed oxidative phosphorylation as a major deregulated pathway among the different datasets. Further, gene expression analysis of mitochondrial electron transport chain show downregulation of genes belonging to Complex I and IV. The results were then validated using the yeast model system. Inhibitor studies using metformin (complex-I inhibitor) and malonate (complex-II inhibitor) did not have any effect in mitigating the amyloids while antimycin (complex-III inhibitor) and azide (complex-IV inhibitor) reduced amyloidogenesis. Knock-out of QCR8 (complex-III) or COX8 (complex–IV) completely cleared the amyloids. Taken together, our results show a critical role for mitochondrial oxidative phosphorylation in amyloidogenesis and as a potential therapeutic target in ALS.

scholarly journals Protein misfolding, amyotrophic lateral sclerosis and guanabenz: protocol for a phase II RCT with futility design (ProMISe trial)

BMJ Open ◽  
2017 ◽  
Vol 7 (8) ◽  
pp. e015434 ◽  
Author(s):  
Eleonora Dalla Bella ◽  
Irene Tramacere ◽  
Giovanni Antonini ◽  
Giuseppe Borghero ◽  
Margherita Capasso ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Amyotrophic Lateral Sclerosis ◽  
Placebo Group ◽  
Phase Ii ◽  
Critical Role ◽  
Protein Translation ◽  
Phase Iii ◽  
Protein Accumulation ◽  
Neuroprotective Effects ◽  
Lateral Sclerosis

IntroductionRecent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS.Methods and analysesProtocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial.Ethics and disseminationThe study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

Neurodegeneration induced by complex I inhibition in a cellular model of familial amyotrophic lateral sclerosis

2006 ◽  
Vol 69 (4) ◽  
pp. 465-474 ◽  
Author(s):  
Milena Rizzardini ◽  
Monica Lupi ◽  
Alessandra Mangolini ◽  
Elisabetta Babetto ◽  
Paolo Ubezio ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Complex I ◽  
Familial Amyotrophic Lateral Sclerosis ◽  
Cellular Model ◽  
Lateral Sclerosis

scholarly journals A perspective on therapies for amyotrophic lateral sclerosis: can disease progression be curbed?

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiaojiao Xu ◽  
Dingding Shen ◽  
Yining Gao ◽  
Qinming Zhou ◽  
You Ni ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Disease Progression ◽  
Motor Neurons ◽  
Critical Role ◽  
Cell Therapies ◽  
Gene Therapies ◽  
Open Questions ◽  
Novel Therapeutic Strategies ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper and lower motor neurons, leading to paralysis and eventually death. Symptomatic treatments such as inhibition of salivation, alleviation of muscle cramps, and relief of spasticity and pain still play an important role in enhancing the quality of life. To date, riluzole and edaravone are the only two drugs approved by the Food and Drug Administration for the treatment of ALS in a few countries. While there is adequate consensus on the modest efficacy of riluzole, there are still open questions concerning the efficacy of edaravone in slowing the disease progression. Therefore, identification of novel therapeutic strategies is urgently needed. Impaired autophagic process plays a critical role in ALS pathogenesis. In this review, we focus on therapies modulating autophagy in the context of ALS. Furthermore, stem cell therapies, gene therapies, and newly-developed biomaterials have great potentials in alleviating neurodegeneration, which might halt the disease progression. In this review, we will summarize the current and prospective therapies for ALS.

scholarly journals Interleukin-1 (IL-1) Receptor-Associated Kinase-Dependent IL-1-Induced Signaling Complexes Phosphorylate TAK1 and TAB2 at the Plasma Membrane and Activate TAK1 in the Cytosol

2002 ◽  
Vol 22 (20) ◽  
pp. 7158-7167 ◽  
Author(s):  
Zhengfan Jiang ◽  
Jun Ninomiya-Tsuji ◽  
Youcun Qian ◽  
Kunihiro Matsumoto ◽  
Xiaoxia Li
Keyword(s):  
Plasma Membrane ◽  
Complex I ◽  
Interleukin 1 ◽  
Critical Role ◽  
Complex Iii ◽  
Receptor Complex ◽  
Complex Ii ◽  
Jnk Activation ◽  
Cytosolic Factors ◽  
Sequential Formation

ABSTRACT Interleukin-1 (IL-1) receptor-associated kinase (IRAK) plays an important role in the sequential formation and activation of IL-1-induced signaling complexes. Previous studies showed that IRAK is recruited to the IL-1-receptor complex, where it is hyperphosphorylated. We now find that the phosphorylated IRAK in turn recruits TRAF6 to the receptor complex (complex I), which differs from the previous concept that IRAK interacts with TRAF6 after it leaves the receptor. IRAK then brings TRAF6 to TAK1, TAB1, and TAB2, which are preassociated on the membrane before stimulation to form the membrane-associated complex II. The formation of complex II leads to the phosphorylation of TAK1 and TAB2 on the membrane by an unknown kinase, followed by the dissociation of TRAF6-TAK1-TAB1-TAB2 (complex III) from IRAK and consequent translocation of complex III to the cytosol. The formation of complex III and its interaction with additional cytosolic factors lead to the activation of TAK1, resulting in NF-κB and JNK activation. Phosphorylated IRAK remains on the membrane and eventually is ubiquitinated and degraded. Taken together, the new data reveal that IRAK plays a critical role in mediating the association and dissociation of IL-1-induced signaling complexes, functioning as an organizer and transporter in IL-1-dependent signaling.

scholarly journals Oxidative Phosphorylation System in Gastric Carcinomas and Gastritis

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
René G. Feichtinger ◽  
Daniel Neureiter ◽  
Tom Skaria ◽  
Silja Wessler ◽  
Timothy L. Cover ◽  
...  
Keyword(s):  
Oxidative Phosphorylation ◽  
Complex I ◽  
Aerobic Glycolysis ◽  
Complex Iii ◽  
Complex Ii ◽  
Gastric Carcinomas ◽  
Cellular Energy ◽  
Protein Levels ◽  
Chemically Induced ◽  
Grade 3

Switching of cellular energy production from oxidative phosphorylation (OXPHOS) by mitochondria to aerobic glycolysis occurs in many types of tumors. However, the significance of this switching for the development of gastric carcinoma and what connection it may have toHelicobacter pyloriinfection of the gut, a primary cause of gastric cancer, are poorly understood. Therefore, we investigated the expression of OXPHOS complexes in two types of human gastric carcinomas (“intestinal” and “diffuse”), bacterial gastritis with and without metaplasia, and chemically induced gastritis by using immunohistochemistry. Furthermore, we analyzed the effect of HP infection on several key mitochondrial proteins. Complex I expression was significantly reduced in intestinal type (but not diffuse) gastric carcinomas compared to adjacent control tissue, and the reduction was independent of HP infection. Significantly, higher complex I and complex II expression was present in large tumors. Furthermore, higher complex II and complex III protein levels were also obvious in grade 3 versus grade 2. No differences of OXPHOS complexes and markers of mitochondrial biogenesis were found between bacterially caused and chemically induced gastritis. Thus, intestinal gastric carcinomas, but not precancerous stages, are frequently characterized by loss of complex I, and this pathophysiology occurs independently of HP infection.

scholarly journals Expression of Oxidative Phosphorylation Complexes and Mitochondrial Mass in Pediatric and Adult Inflammatory Bowel Disease

2022 ◽  
Vol 2022 ◽  
pp. 1-14
Author(s):  
Anna M. Schneider ◽  
Mihriban Özsoy ◽  
Franz A. Zimmermann ◽  
Susanne M. Brunner ◽  
René G. Feichtinger ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Oxidative Phosphorylation ◽  
Terminal Ileum ◽  
Complex I ◽  
Older Patients ◽  
Pediatric Patients ◽  
The Other ◽  
Complex Iii ◽  
Mitochondrial Mass ◽  
Inflammatory Bowel

Introduction. Inflammatory bowel disease (IBD), which includes Crohn’s disease (CD) and ulcerative colitis (UC), is a multifactorial intestinal disorder but its precise etiology remains elusive. As the cells of the intestinal mucosa have high energy demands, mitochondria may play a role in IBD pathogenesis. The present study is aimed at evaluating the expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes in IBD. Material and Methods. 286 intestinal biopsy samples from the terminal ileum, ascending colon, and rectum from 124 probands (34 CD, 33 UC, and 57 controls) were stained immunohistochemically for all five OXPHOS complexes and the voltage-dependent anion-selective channel 1 protein (VDAC1 or porin). Expression levels were compared in multivariate models including disease stage (CD and UC compared to controls) and age (pediatric/adult). Results. Analysis of the terminal ileum of CD patients revealed a significant reduction of complex II compared to controls, and a trend to lower levels was evident for VDAC1 and the other OXPHOS complexes except complex III. A similar pattern was found in the rectum of UC patients: VDAC1, complex I, complex II, and complex IV were all significantly reduced, and complex III and V showed a trend to lower levels. Reductions were more prominent in older patients compared to pediatric patients and more marked in UC than CD. Conclusion. A reduced mitochondrial mass is present in UC and CD compared to controls. This is potentially a result of alterations of mitochondrial biogenesis or mitophagy. Reductions were more pronounced in older patients compared to pediatric patients, and more prominent in UC than CD. Complex I and II are more severely compromised than the other OXPHOS complexes. This has potential therapeutic implications, since treatments boosting biogenesis or influencing mitophagy could be beneficial for IBD treatment. Additionally, substances specifically stimulating complex I activity should be tested in IBD treatment.

scholarly journals Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 10 (10) ◽  
pp. 675
Author(s):  
Hyun-Jun Choi ◽  
Sun Joo Cha ◽  
Jang-Won Lee ◽  
Hyung-Jun Kim ◽  
Kiyoung Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase 3 ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

Denouement of Chemicals on Amyotrophic Lateral Sclerosis: Is Green Chemistry the Answer

2020 ◽  
Vol 16 (8) ◽  
pp. 1058-1068
Author(s):  
Faizana Fayaz ◽  
Faheem H. Pottoo ◽  
Sadat Shafi ◽  
Mushtaq A. Wani ◽  
Sharad Wakode ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Green Chemistry ◽  
Ozone Depletion ◽  
Critical Role ◽  
Chemical Substance ◽  
Standards Of Living ◽  
Improper Use ◽  
High Standards ◽  
Lateral Sclerosis

Medicinal Chemistry has played a critical role in evolving new products, resources and processes which inexorably correspond to our high standards of living. Unfortunately, this has also caused deterioration of human health and threats to the global environment, even deaths when highly exposed to certain chemicals, whether due to improper use, mishandling or disposal. There are chemicals, which apart from being carcinogens, endocrine disruptors or neurotoxins, are also responsible for climate change and ozone depletion. Certain chemicals are known to cause neurotoxicity and are having tendencies to damage the central and peripheral nervous system or brain by damaging neurons or cells which are responsible for transmitting and processing of signals. This has raised serious concerns for the use and handling of such chemicals and has given growth to a relatively new emerging field known as Green Chemistry that strives to achieve sustainability at the molecular level and has an ability to harness chemicals to meet environmental and economic goals. It has been reported in the literature that apart from family history in the aetiology of Amyotrophic lateral Sclerosis (ALS), also termed as “Lou Gehrig’s disease”, a neurological disorder, environmental factors, heavy metals, particularly selenium, lead, mercury, cadmium, formaldehyde, pesticides and certain herbicides are known to cause ALS. ALS, a progressive neurodegenerative disease affects the motor cortex, brain stem and spinal cord, causing muscular weakness, spasticity, and hyperreflexia. In this article we are aiming to discuss and summarize the various corroborations and findings supporting the undesirable role of chemical substance/herbicides/pesticides in ALS aetiology and its mitigation by adopting green chemistry.

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