Understanding correlation of abnormal c-JNK/p38MAPK signaling in amyotrophic lateral sclerosis: Potential drug targets and influences on neurological disorders

2021 ◽  
Vol 20 ◽  
Author(s):  
Rajeshwar Kumar Yadav ◽  
Elizabeth Minj ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Motor Neuron ◽  
Drug Targets ◽  
Management Strategies ◽  
Mitogen Activated Protein Kinase ◽  
Glutamate Excitotoxicity ◽  
Mitogen Activated Protein ◽  
P38mapk Signaling ◽  
Lateral Sclerosis

: c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to incorporate neuronal signals that cause glutamate excitotoxicity, impaired protein homeostasis, defective axonal transport, and synaptic dysfunctions. Consistent with the importance of these cellular events in the up-regulation of c-JNK/p38MAPK signaling is associated with neurodegenerative diseases in various clinical and pre-clinical studies. Exceptionally, a large number of experimental evidence has recently shown that c-JNK/p38MAPK has also been involved in the development of the central nervous system in a variety of neuropathological conditions, including amyotrophic lateral sclerosis (ALS). Overall, the currently available information has shown that c-JNK/p38MAPK signaling inhibitors can be a promising therapeutic solution for modifying histopathological, functional, and demyelination defects associated with motor neuron disabilities. Understanding the correlation between c-JNK/p38MAPK signaling and prediction of motor neuron degradation can help identify significant therapeutic measures that may avoid neuro complications. Therefore, in the current study, we explore the manifestations of disease utilizing the c-JNK/p38MAPK upregulation that could potentially cause ALS and other neurodegenerative diseases, as well as providing data on pre-clinical trials, accessible and successful drug treatment, and disease management strategies.

scholarly journals Suppression of MAP4K4 Signaling Ameliorates Motor Neuron Degeneration in Amyotrophic Lateral Sclerosis-Molecular Studies Toward New Therapeutics

2019 ◽  
Vol 13 ◽  
pp. 117906951986279 ◽  
Author(s):  
Michelle E Watts ◽  
Chen Wu ◽  
Lee L Rubin
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Specific Inhibitor ◽  
Induced Pluripotent Stem Cell ◽  
Mitogen Activated Protein Kinase ◽  
Apoptotic Pathway ◽  
Neuronal Viability ◽  
Mitogen Activated Protein ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), the most common motor neuron (MN) disease of adults, is characterized by the degeneration of upper MNs in the motor cortex and lower MNs in the brain stem and spinal cord. Our recent work suggests that a MAP kinase family member, MAP4K4 (mitogen-activated protein kinase kinase kinase kinase 4), regulates MN degeneration in ALS. Activation of MAP4K4 occurs prior to MN death and inhibition of MAP4K4 improves neurite integrity and neuronal viability in a cell autonomous manner. The mechanism through which MAP4K4 reduction specifically modulates MN viability can be attributed to the attenuation of the c-Jun apoptotic pathway, as well as to the activation of FoxO1-mediated autophagy that reduces the accumulation of protein aggregates. We additionally show the feasibility of MAP4K4 as a drug target using a MAP4K4-specific inhibitor, which improves the survival of both primary and induced pluripotent stem cell (iPSC)-derived MNs. Our studies are thus far the first to highlight a MAP4K4-initiated signaling cascade that contributes to MN degeneration in ALS, providing a new mechanism underlying MN death in disease and a druggable target for new therapeutics. We propose exciting future directions and unexplored avenues based upon this work.

scholarly journals Adipose-derived Stem Cell Conditioned Media Extends Survival time of a mouse model of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Christine V. Fontanilla ◽  
Huiying Gu ◽  
Qingpeng Liu ◽  
Timothy Z. Zhu ◽  
Changwei Zhou ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Survival Time ◽  
Neuronal Death ◽  
Immunohistochemical Analysis ◽  
Mitogen Activated Protein Kinase ◽  
Trophic Factors ◽  
Mitogen Activated Protein ◽  
Adipose Derived Stem Cell ◽  
Lateral Sclerosis

Abstract Adipose stromal cells (ASC) secrete various trophic factors that assist in the protection of neurons in a variety of neuronal death models. In this study, we tested the effects of human ASC conditional medium (ASC-CM) in human amyotrophic lateral sclerosis (ALS) transgenic mouse model expressing mutant superoxide dismutase (SOD1G93A). Treating symptomatic SOD1G93A mice with ASC-CM significantly increased post-onset survival time and lifespan. Moreover, SOD1G93A mice given ASC-CM treatment showed high motor neuron counts, less activation of microglia and astrocytes at an early symptomatic stage in the spinal cords under immunohistochemical analysis. SOD1G93A mice treated with ASC-CM for 7 days showed reduced levels of phosphorylated p38 (pp38) in the spinal cord, a mitogen-activated protein kinase that is involved in both inflammation and neuronal death. Additionally, the levels of α-II spectrin in spinal cords were also inhibited in SOD1G93A mice treated with ASC-CM for 3 days. Interestingly, nerve growth factor (NGF), a neurotrophic factor found in ASC-CM, played a significant role in the protection of neurodegeneration inSOD1G93A mouse. These results indicate that ASC-CM has the potential to develop into a novel and effective therapeutic treatment for ALS.

scholarly journals Glutamate Slows Axonal Transport of Neurofilaments in Transfected Neurons

2000 ◽  
Vol 150 (1) ◽  
pp. 165-176 ◽  
Author(s):  
Steven Ackerley ◽  
Andrew J. Grierson ◽  
Janet Brownlees ◽  
Paul Thornhill ◽  
Brian H. Anderton ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Axonal Transport ◽  
Fluorescent Protein ◽  
Mitogen Activated Protein Kinase ◽  
Glutamate Excitotoxicity ◽  
Slow Axonal Transport ◽  
Mitogen Activated Protein ◽  
Green Fluorescent ◽  
Pathogenic Process ◽  
Neurofilament Transport

Neurofilaments are transported through axons by slow axonal transport. Abnormal accumulations of neurofilaments are seen in several neurodegenerative diseases, and this suggests that neurofilament transport is defective. Excitotoxic mechanisms involving glutamate are believed to be part of the pathogenic process in some neurodegenerative diseases, but there is currently little evidence to link glutamate with neurofilament transport. We have used a novel technique involving transfection of the green fluorescent protein–tagged neurofilament middle chain to measure neurofilament transport in cultured neurons. Treatment of the cells with glutamate induces a slowing of neurofilament transport. Phosphorylation of the side-arm domains of neurofilaments has been associated with a slowing of neurofilament transport, and we show that glutamate causes increased phosphorylation of these domains in cell bodies. We also show that glutamate activates members of the mitogen-activated protein kinase family, and that these kinases will phosphorylate neurofilament side-arm domains. These results provide a molecular framework to link glutamate excitotoxicity with neurofilament accumulation seen in some neurodegenerative diseases.

scholarly journals Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 969
Author(s):  
TG Sahana ◽  
Ke Zhang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Spinal Cord Tissue ◽  
Disease Manifestation ◽  
Drug Candidates ◽  
Mitogen Activated Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.

scholarly journals Examining the Relationship between Concussion and Neurodegenerative Disorders: A Review on Amyotrophic Lateral Sclerosis (ALS) and Alzheimer’s Disease (AD)

2021 ◽  
Author(s):  
Edward Poluyi ◽  
Eghosa Morgan ◽  
Charles Poluyi ◽  
Chibuikem Ikwuegbuenyi ◽  
Grace Imaguezegie
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Brain Injuries ◽  
Tau Proteins ◽  
Glutamate Excitotoxicity ◽  
Clinical Test ◽  
Lateral Sclerosis

Abstract Background Current epidemiological studies have examined the associations between moderate and severe traumatic brain injury (TBI) and their risks of developing neurodegenerative diseases. Concussion, also known as mild TBI (mTBI), is however quite distinct from moderate or severe TBIs. Only few studies in this burgeoning area have examined concussion—especially repetitive episodes—and neurodegenerative diseases. Thus, no definite relationship has been established between them. Objectives This review will discuss the available literatures linking concussion and amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease (AD). Materials and Methods Given the complexity of this subject, a realist review methodology was selected which includes clarifying the scope and developing a theoretical framework, developing a search strategy, selection and appraisal, data extraction, and synthesis. A detailed literature matrix was set out in order to get relevant and recent findings on this topic. Results Presently, there is no objective clinical test for the diagnosis of concussion because the features are less obvious on physical examination. Absence of an objective test in diagnosing concussion sometimes leads to skepticism when confirming the presence or absence of concussion. Intriguingly, several possible explanations have been proposed in the pathological mechanisms that lead to the development of some neurodegenerative disorders (such as ALS and AD) and concussion but the two major events are deposition of tau proteins (abnormal microtubule proteins) and neuroinflammation, which ranges from glutamate excitotoxicity pathways and inflammatory pathways (which leads to a rise in the metabolic demands of microglia cells and neurons), to mitochondrial function via the oxidative pathways. Conclusion mTBI constitutes majority of brain injuries. However, studies have focused mostly on moderate-to-severe TBI as highlighted above with inconclusive and paucity of studies linking concussion and neurodegenerative disorders. Although, it is highly probable that repetitive concussion (mTBI) and subconcussive head injuries may be risk factors for ALS) and AD from this review. It will be imperative therefore to conduct more research with a focus on mTBI and its association with ALS and AD.

scholarly journals Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 227
Author(s):  
Nuno Santos Leal ◽  
Luís Miguel Martins
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Drug Targets ◽  
Biological Functions ◽  
Cell Dysfunction ◽  
Contact Sites ◽  
New Findings ◽  
Lateral Sclerosis

The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.

scholarly journals Glial cell inclusions and the pathogenesis of neurodegenerative diseases

2004 ◽  
Vol 1 (1) ◽  
pp. 13-21 ◽  
Author(s):  
DAVID W. MILLER ◽  
MARK R. COOKSON ◽  
DENNIS W. DICKSON
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Glial Cell ◽  
Neurodegenerative Disorders ◽  
Glutamate Excitotoxicity ◽  
Fundamental Nature ◽  
The Future ◽  
Lateral Sclerosis

In this review, we discuss examples that show how glial-cell pathology is increasingly recognized in several neurodegenerative diseases. We also discuss the more provocative idea that some of the disorders that are currently considered to be neurodegenerative diseases might, in fact, be due to primary abnormalities in glia. Although the mechanism of glial pathology (i.e. modulating glutamate excitotoxicity) might be better established for amyotrophic lateral sclerosis (ALS), a role for neuronal–glial interactions in the pathogenesis of most neurodegenerative diseases is plausible. This burgeoning area of neuroscience will receive much attention in the future and it is expected that further understanding of basic neuronal–glial interactions will have a significant impact on the understanding of the fundamental nature of human neurodegenerative disorders.

Targeting abnormal Nrf2/HO-1 signaling in amyotrophic lateral sclerosis: Current Insights on drug targets and influences on neurological disorders

2021 ◽  
Vol 21 ◽  
Author(s):  
Elizabeth Minj ◽  
Rajeshwar Kumar Yadav ◽  
Sidharth Mehan
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Drug Targets ◽  
Cell Activation ◽  
Symptomatic Relief ◽  
Neuronal Cell ◽  
Related Factor ◽  
Glial Cell Activation ◽  
Lateral Sclerosis

: The nuclear erythroid 2-related-factor (Nrf2) transcription factor/hemoxygenase 1 (HO-1) is a key regulator of an important neuroprotection response by driving the interpretation of various cytoprotective gene to encode for antiinflammatory, anti-oxidant, and detoxifying proteins. Various studies investigated that the upregulation of Nrf2/HO-1 has become the potential therapeutic approach in amyotrophic lateral sclerosis (ALS). As amyotrophic lateral sclerosis is a motor neuron disease in which there is a progressive loss of upper motor neuron and lower motor neurons of the motor cortex, brain stem, and corticospinal tract. As a result of this upregulation of Nrf2/HO-1 indicates that in brain antioxidant capacity is reinforced. Further, this shows a cytoprotective effect against oxidative stress in amyotrophic lateral sclerosis. A study reported functions associated with the Nrf2/HO-1 in the neuronal cell, oligodendrocytes, microglia, and astrocytes. Although ALS's pathogenesis is not yet clear but compelling, the evidence shows any dysfunction in the brain such as mitochondrial dysfunction, protein aggregation, glial cell activation, excitotoxicity, and apoptosis gives ALS like symptoms. In this review, we have mainly focused on detailing the downregulation of Nrf2/HO-1, which may be the prime reason and may further serve as a pathological hallmark for ALS development. As surveyed, there are limited target-based interventions that only provide symptomatic relief but do not cure the disease completely. Dysregulation of the Nrf2/HO-1 signaling pathway leads to many physiological changes contributing to neurological conditions, including ALS. Based on the above view, we summarized the combined role of Nrf2/HO-1 signaling in ALS and explored potential therapeutic strategies for disease improvement through pathway modulators.

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