scholarly journals Molecular and Cellular Mechanisms Affected in ALS

2020 ◽  
Vol 10 (3) ◽  
pp. 101 ◽  
Author(s):  
Laura Le Gall ◽  
Ekene Anakor ◽  
Owen Connolly ◽  
Udaya Vijayakumar ◽  
William Duddy ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Molecular Mechanisms ◽  
Late Onset ◽  
Glutamate Excitotoxicity ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Onset Condition ◽  
Wide Range ◽  
Sporadic Cases ◽  
Aberrant Rna

Amyotrophic lateral sclerosis (ALS) is a terminal late-onset condition characterized by the loss of upper and lower motor neurons. Mutations in more than 30 genes are associated to the disease, but these explain only ~20% of cases. The molecular functions of these genes implicate a wide range of cellular processes in ALS pathology, a cohesive understanding of which may provide clues to common molecular mechanisms across both familial (inherited) and sporadic cases and could be key to the development of effective therapeutic approaches. Here, the different pathways that have been investigated in ALS are summarized, discussing in detail: mitochondrial dysfunction, oxidative stress, axonal transport dysregulation, glutamate excitotoxicity, endosomal and vesicular transport impairment, impaired protein homeostasis, and aberrant RNA metabolism. This review considers the mechanistic roles of ALS-associated genes in pathology, viewed through the prism of shared molecular pathways.

Abstract 497: Cholesterol and Toll-like Receptor Signaling Are Important Regulators of Macrophage Interactions with Atherosclerotic Lipoprotein Aggregates

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Harvey F Chin ◽  
Abigail Haka ◽  
Frederick R Maxfield
Keyword(s):  
Molecular Mechanisms ◽  
Atherosclerotic Plaques ◽  
Cholesteryl Esters ◽  
Cellular Mechanisms ◽  
Downstream Signaling ◽  
Cellular Processes ◽  
Atherosclerotic Plaque Formation ◽  
Subendothelial Space ◽  
Morphological Responses ◽  
Cytoskeletal Rearrangements

Macrophages encounter deposits of aggregated low-density lipoproteins (agLDL) in the subendothelial space of blood vessels during the first stages of atherosclerotic plaque formation. Notably, current models for the mechanism of macrophage internalization of cholesterol in early atherosclerotic plaques are incomplete due to the lack of attention paid to the unique cellular mechanisms that are required for macrophages to degrade aggregates of LDL in particular, which can comprise >90% of the LDL in atherosclerotic plaques. In fact, internalization of cholesterol from cholesteryl esters in agLDL involves the development of intriguing cellular processes in which extracellular acidic compartments, lysosomal synapses (LSs), are formed whereby agLDL is partially degraded prior to internalization. This process requires extensive cytoskeletal rearrangements and secretion of lysosomal enzymes responsible for hydrolysis of cholesteryl esters from the agLDL. Subsequent delivery of free cholesterol from agLDL to the macrophage plasma membrane is central for development of the LS. Nonetheless, the molecular mechanism underlying initiation and propagation of the LS are currently largely unknown. This research proposal aims to elucidate the molecular mechanisms of LS formation and the role that cholesterol plays in eliciting these morphological responses to agLDL. Fluorescence microscopy assays were used to identify activation of TLR4 and downstream signaling involving PI3K and Akt as important events leading to LS formation. Furthermore, morphological responses of macrophages to cholesterol overloading require overlapping signaling pathways, indicating the role of interplay of cholesterol and TLR4 signaling in development of this novel macrophage interaction with aggregated LDL found in plaques. Identification of specific molecular pathways involved in this process will not only contribute to the basic understanding of one of the primary cellular processes contributing to atherosclerosis, one of the primary causes of heart disease, but also provide tangible molecular targets for the ultimate development of therapies.

Molecular mechanisms of endolysosomal Ca2+ signalling in health and disease

2011 ◽  
Vol 439 (3) ◽  
pp. 349-378 ◽  
Author(s):  
Anthony J. Morgan ◽  
Frances M. Platt ◽  
Emyr Lloyd-Evans ◽  
Antony Galione
Keyword(s):  
Molecular Mechanisms ◽  
Cellular Processes ◽  
Late Endosomes ◽  
Wide Range ◽  
Health And Disease ◽  
Lysosome Related Organelles ◽  
Cellular Compartments ◽  
Endosomal Vesicles ◽  
Intracellular Targets

Endosomes, lysosomes and lysosome-related organelles are emerging as important Ca2+ storage cellular compartments with a central role in intracellular Ca2+ signalling. Endocytosis at the plasma membrane forms endosomal vesicles which mature to late endosomes and culminate in lysosomal biogenesis. During this process, acquisition of different ion channels and transporters progressively changes the endolysosomal luminal ionic environment (e.g. pH and Ca2+) to regulate enzyme activities, membrane fusion/fission and organellar ion fluxes, and defects in these can result in disease. In the present review we focus on the physiology of the inter-related transport mechanisms of Ca2+ and H+ across endolysosomal membranes. In particular, we discuss the role of the Ca2+-mobilizing messenger NAADP (nicotinic acid adenine dinucleotide phosphate) as a major regulator of Ca2+ release from endolysosomes, and the recent discovery of an endolysosomal channel family, the TPCs (two-pore channels), as its principal intracellular targets. Recent molecular studies of endolysosomal Ca2+ physiology and its regulation by NAADP-gated TPCs are providing exciting new insights into the mechanisms of Ca2+-signal initiation that control a wide range of cellular processes and play a role in disease. These developments underscore a new central role for the endolysosomal system in cellular Ca2+ regulation and signalling.

Roots to start research in amyotrophic lateral sclerosis: molecular pathways and novel therapeutics for future

2015 ◽  
Vol 26 (2) ◽  
Author(s):  
Dibbanti Harikrishnareddy ◽  
Shubham Misra ◽  
Sujata Upadhyay ◽  
Manish Modi ◽  
Bikash Medhi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Signs And Symptoms ◽  
Clinical Excellence ◽  
Premature Death ◽  
Glutamate Excitotoxicity ◽  
Severe Motor ◽  
Associated Risk Factors ◽  
Aberrant Rna ◽  
Lateral Sclerosis

AbstractAmyotrophic lateral sclerosis (ALS) is a devastating neurological disease that rapidly progresses from mild motor symptoms to severe motor paralysis and premature death. There is currently no cure for this devastating disease; most ALS patients die of respiratory failure generally within 3–5 years from the onset of signs and symptoms. Approximately 90% of ALS cases are sporadic in nature, with no clear associated risk factors. It is reported that ALS is a complex and multifaceted neurodegenerative disease. Less is known about the key factors involved in the sporadic form of the disease. The intricate pathogenic mechanisms that target motor neurons in ALS includes oxidative stress, glutamate excitotoxicity, mitochondrial damage, protein aggregation, glia and neuroinflammation pathology, defective axonal transport, and aberrant RNA metabolism. Despite aggressive research, no therapy has been yet proven to completely reverse the core symptoms of the disease. Riluzole is the only drug approved by the Food and Drug Administration and recommended by the National Institute for Clinical Excellence so far proven to be successful against ALS and may prevent progression and extend life for a few months or so. This article provides a novel understanding in key findings of pathogenesis and interventions currently under investigation to slow disease progression in ALS.

scholarly journals Oxidation inhibits autophagy protein deconjugation from phagosomes to sustain MHC class II restricted antigen presentation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Laure-Anne Ligeon ◽  
Maria Pena-Francesch ◽  
Liliana Danusia Vanoaica ◽  
Nicolás Gonzalo Núñez ◽  
Deepti Talwar ◽  
...  
Keyword(s):  
Antigen Presentation ◽  
Mhc Class Ii ◽  
Antigen Processing ◽  
Redox Regulation ◽  
Molecular Mechanisms ◽  
Class Ii ◽  
Oxygen Species ◽  
Cellular Processes ◽  
Oxidative Inactivation ◽  
Wide Range

AbstractLC3-associated phagocytosis (LAP) contributes to a wide range of cellular processes and notably to immunity. The stabilization of phagosomes by the macroautophagy machinery in human macrophages can maintain antigen presentation on MHC class II molecules. However, the molecular mechanisms involved in the formation and maturation of the resulting LAPosomes are not completely understood. Here, we show that reactive oxygen species (ROS) produced by NADPH oxidase 2 (NOX2) stabilize LAPosomes by inhibiting LC3 deconjugation from the LAPosome cytosolic surface. NOX2 residing in the LAPosome membrane generates ROS to cause oxidative inactivation of the protease ATG4B, which otherwise releases LC3B from LAPosomes. An oxidation-insensitive ATG4B mutant compromises LAP and thereby impedes sustained MHC class II presentation of exogenous Candida albicans antigens. Redox regulation of ATG4B is thereby an important mechanism for maintaining LC3 decoration of LAPosomes to support antigen processing for MHC class II presentation.

scholarly journals Glial Bridge Ecology: Cellular Mechanisms that Drive Spinal Cord Regeneration in Zebrafish

2018 ◽  
Author(s):  
Corbin J. Schuster ◽  
Robert M. Kao
Keyword(s):  
Spinal Cord ◽  
Molecular Mechanisms ◽  
Cell Injury ◽  
Model Organism ◽  
Spinal Cord Regeneration ◽  
Cellular Mechanisms ◽  
Bridge Formation ◽  
Cellular Processes ◽  
Cord Injury ◽  
One Step

Zebrafish have been found to be the premier model organism in biological and biomedical research, specifically offering many advantages in developmental biology and genetics. This unique aquatic species has been found to have the capacity to regenerate their spinal cord after injury. However, the complete molecular and cellular mechanisms behind glial bridge formation in the central and peripheral nervous systems upon glial cell injury remains unclear. This review paper focuses on the molecular mechanisms and cellular processes that underlie spinal cord regeneration in four initial phases: proliferation and initial migration; migration and differentiation; glial bridge formation; and remodeling. We propose that within these four phases the cellular mechanisms that underlie spinal cord regeneration each express a terminating signal that aborts one step of the process and initiates the next. Specifically, future studies would be devoted to investigate transmitting signals in the spinal cord injury micro-environment in hope to contribute to the understanding of underlying cellular mechanisms by connecting each process of spinal cord regeneration in zebrafish.

scholarly journals Viruses Run: The Evasion Mechanisms of the Antiviral Innate Immunity by Hantavirus

2021 ◽  
Vol 12 ◽  
Author(s):  
Yusi Zhang ◽  
Ruixue Ma ◽  
Yutong Wang ◽  
Wenjie Sun ◽  
Ziwei Yang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Immune Surveillance ◽  
Hemorrhagic Fever ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Regulated Cell Death ◽  
Antiviral Innate Immunity

Hantavirus can cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome (HPS) in America, with high mortality and unknown mechanisms. Innate immunity is the host’s first-line defense to bridge the acquired immunity against viral infections. However, hantavirus has evolved various strategies in both molecular and cellular aspects to evade the host’s natural immune surveillance. The Interferon-I (IFN-I) signaling pathway, a central link of host defense, induces various antiviral proteins to control the infection. This paper summarizes the molecular mechanisms of hantavirus evasion mechanisms of the IFN signaling pathway and cellular processes such as regulated cell death and cell stress. Besides, hantavirus could also evade immune surveillance evasion through cellular mechanisms, such as upregulating immune checkpoint molecules interfering with viral infections. Understanding hantavirus’s antiviral immune evasion mechanisms will deepen our understanding of its pathogenesis and help us develop more effective methods to control and eliminate hantavirus.

scholarly journals Loss of CREST leads to neuroinflammatory responses and ALS-like motor defects in mice

2018 ◽  
Author(s):  
Cheng Cheng ◽  
Kan Yang ◽  
Xinwei Wu ◽  
Yuefang Zhang ◽  
Shifang Shan ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Microglial Activation ◽  
Molecular Mechanisms ◽  
Motor Coordination ◽  
Inflammatory Responses ◽  
Late Onset ◽  
Critical Role ◽  
Histone Deacetylation ◽  
Loss Of Function ◽  
Sporadic Als

SUMMARYAmyotrophic lateral sclerosis (ALS) is a late onset neurodegenerative disease with fast progression. Mutations of the CREST gene (also known as SS18L1) are identified in sporadic ALS patients. Whether CREST mutations may lead to ALS remained largely unclear. In this study, we showed that the ALS-related CREST-Q388X mutation exhibited loss-of-function effects. Importantly, we found that microglial activation were prevalent in CREST haploinsufficieny mice and the Q394X mice mimicking the human CREST Q388X mutation. Furthermore, we showed that both CREST haploinsufficieny and the Q394X mice displayed deficits in motor coordination. Finally, we identified the critical role of CREST-BRG1 complex in repressing the expression of immune-related cytokines including Ccl2 and Cxcl10 in neurons, via histone deacetylation, providing the molecular mechanisms underlying inflammatory responses lack of CREST. These findings indicate that elevated inflammatory responses in a subset of ALS may be caused by neuron-derived factors, suggesting potential therapeutic methods through inflammation pathways.In BriefCheng et al. discovered that neuronal loss of CREST reduces the protein level of FUS, de-represses the transcriptional inhibition of chemokine genes which in turn causes microglial activation and proinflammation, and ultimately leads to axonal degeneration of motor neurons and impairment of locomotion.

scholarly journals Implications of Selective Autophagy Dysfunction for ALS Pathology

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 381 ◽  
Author(s):  
Emiliano Vicencio ◽  
Sebastián Beltrán ◽  
Luis Labrador ◽  
Patricio Manque ◽  
Melissa Nassif ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Cellular Mechanisms ◽  
Selective Autophagy ◽  
Neurodegenerative Process ◽  
Sporadic Cases ◽  
Protein Components ◽  
Als Patients ◽  
Brain And Spinal Cord

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder that progressively affects motor neurons in the brain and spinal cord. Due to the biological complexity of the disease, its etiology remains unknown. Several cellular mechanisms involved in the neurodegenerative process in ALS have been found, including the loss of RNA and protein homeostasis, as well as mitochondrial dysfunction. Insoluble protein aggregates, damaged mitochondria, and stress granules, which contain RNA and protein components, are recognized and degraded by the autophagy machinery in a process known as selective autophagy. Autophagy is a highly dynamic process whose dysregulation has now been associated with neurodegenerative diseases, including ALS, by numerous studies. In ALS, the autophagy process has been found deregulated in both familial and sporadic cases of the disease. Likewise, mutations in genes coding for proteins involved in the autophagy machinery have been reported in ALS patients, including selective autophagy receptors. In this review, we focus on the role of selective autophagy in ALS pathology.

scholarly journals Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1618 ◽  
Author(s):  
Ko-Hsiu Lu ◽  
Renn-Chia Lin ◽  
Jia-Sin Yang ◽  
Wei-En Yang ◽  
Russel J. Reiter ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Bone Growth ◽  
Age Distribution ◽  
Underlying Mechanism ◽  
Therapeutic Effects ◽  
Anticancer Activities ◽  
Cellular Mechanisms ◽  
Wide Range ◽  
Review Reports

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11–15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.

scholarly journals p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen

2020 ◽  
Vol 219 (11) ◽  
Author(s):  
Liz J. Valente ◽  
Amy Tarangelo ◽  
Albert Mao Li ◽  
Marwan Naciri ◽  
Nitin Raj ◽  
...  
Keyword(s):  
Tumor Suppression ◽  
Human Cancer ◽  
Actin Dynamics ◽  
Migration And Invasion ◽  
Wild Type ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Wide Range ◽  
Oxygen Conditions ◽  
Genome Stabilization

The mechanisms by which TP53, the most frequently mutated gene in human cancer, suppresses tumorigenesis remain unclear. p53 modulates various cellular processes, such as apoptosis and proliferation, which has led to distinct cellular mechanisms being proposed for p53-mediated tumor suppression in different contexts. Here, we asked whether during tumor suppression p53 might instead regulate a wide range of cellular processes. Analysis of mouse and human oncogene-expressing wild-type and p53-deficient cells in physiological oxygen conditions revealed that p53 loss concurrently impacts numerous distinct cellular processes, including apoptosis, genome stabilization, DNA repair, metabolism, migration, and invasion. Notably, some phenotypes were uncovered only in physiological oxygen. Transcriptomic analysis in this setting highlighted underappreciated functions modulated by p53, including actin dynamics. Collectively, these results suggest that p53 simultaneously governs diverse cellular processes during transformation suppression, an aspect of p53 function that would provide a clear rationale for its frequent inactivation in human cancer.

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