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.

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 Impact of traumatic brain injury on amyotrophic lateral sclerosis: from bedside to bench

2019 ◽  
Vol 122 (3) ◽  
pp. 1174-1185 ◽  
Author(s):  
Colin K. Franz ◽  
Divya Joshi ◽  
Elizabeth L. Daley ◽  
Rogan A. Grant ◽  
Kyriakos Dalamagkas ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Amyotrophic Lateral Sclerosis ◽  
Brain Injury ◽  
Motor Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Epidemiological Studies ◽  
History Of ◽  
Induced Pluripotent ◽  
Progressive Weakness ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, which manifests clinically as progressive weakness. Although several epidemiological studies have found an association between traumatic brain injury (TBI) and ALS, there is not a consensus on whether TBI is an ALS risk factor. It may be that it can cause ALS in a subset of susceptible patients, based on a history of repetitive mild TBI and genetic predisposition. This cannot be determined based on clinical observational studies alone. Better preclinical models are necessary to evaluate the effects of TBI on ALS onset and progression. To date, only a small number of preclinical studies have been performed, mainly in the superoxide dismutase 1 transgenic rodents, which, taken together, have mixed results and notable methodological limitations. The more recent incorporation of additional animal models such as Drosophila flies, as well as patient-induced pluripotent stem cell-derived neurons, should facilitate a better understanding of a potential functional interaction between TBI and ALS.

scholarly journals The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis

2017 ◽  
Vol 9 (391) ◽  
pp. eaaf3962 ◽  
Author(s):  
Keiko Imamura ◽  
Yuishin Izumi ◽  
Akira Watanabe ◽  
Kayoko Tsukita ◽  
Knut Woltjen ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
New Drugs ◽  
Small Interfering Rnas ◽  
Altered Expression ◽  
Sporadic Als ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), a fatal disease causing progressive loss of motor neurons, still has no effective treatment. We developed a phenotypic screen to repurpose existing drugs using ALS motor neuron survival as readout. Motor neurons were generated from induced pluripotent stem cells (iPSCs) derived from an ALS patient with a mutation in superoxide dismutase 1 (SOD1). Results of the screen showed that more than half of the hits targeted the Src/c-Abl signaling pathway. Src/c-Abl inhibitors increased survival of ALS iPSC-derived motor neurons in vitro. Knockdown of Src or c-Abl with small interfering RNAs (siRNAs) also rescued ALS motor neuron degeneration. One of the hits, bosutinib, boosted autophagy, reduced the amount of misfolded mutant SOD1 protein, and attenuated altered expression of mitochondrial genes. Bosutinib also increased survival in vitro of ALS iPSC-derived motor neurons from patients with sporadic ALS or other forms of familial ALS caused by mutations in TAR DNA binding protein (TDP-43) or repeat expansions in C9orf72. Furthermore, bosutinib treatment modestly extended survival of a mouse model of ALS with an SOD1 mutation, suggesting that Src/c-Abl may be a potentially useful target for developing new drugs to treat ALS.

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 Taking Cellular Heterogeneity Into Consideration When Modeling Astrocyte Involvement in Amyotrophic Lateral Sclerosis Using Human Induced Pluripotent Stem Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Stefano Stifani
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Nervous System ◽  
Induced Pluripotent Stem Cell ◽  
Model Systems ◽  
Cellular Heterogeneity ◽  
Structural Support ◽  
Human Astrocytes ◽  
Experimental Model Systems ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Astrocytes are a large group of glial cells that perform a variety of physiological functions in the nervous system. They provide trophic, as well as structural, support to neuronal cells. Astrocytes are also involved in neuroinflammatory processes contributing to neuronal dysfunction and death. Growing evidence suggests important roles for astrocytes in non-cell autonomous mechanisms of motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Understanding these mechanisms necessitates the combined use of animal and human cell-based experimental model systems, at least in part because human astrocytes display a number of unique features that cannot be recapitulated in animal models. Human induced pluripotent stem cell (hiPSC)-based approaches provide the opportunity to generate disease-relevant human astrocytes to investigate the roles of these cells in ALS. These approaches are facing the growing recognition that there are heterogenous populations of astrocytes in the nervous system which are not functionally equivalent. This review will discuss the importance of taking astrocyte heterogeneity into consideration when designing hiPSC-based strategies aimed at generating the most informative preparations to study the contribution of astrocytes to ALS pathophysiology.

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