scholarly journals Autophagy and Schizophrenia: A Closer Look at How Dysregulation of Neuronal Cell Homeostasis Influences the Pathogenesis of Schizophrenia

2017 ◽  
Vol 31 (1&2) ◽  
pp. 34 ◽  
Author(s):  
Jaime L. Schneider ◽  
Ann M. Miller ◽  
Mary E. Woesner
Keyword(s):  
Cell Biology ◽  
Transcriptional Profiling ◽  
Neuronal Cell ◽  
Specific Area ◽  
Standard Of Care ◽  
Psychotic Symptoms ◽  
Neuronal Homeostasis ◽  
The Central Nervous System ◽  
First Time

Autophagy, the process of degrading intracellular components in lysosomes, plays an important role in the central nervous system by contributing to neuronal homeostasis. Autophagic failure has been linked to neurologic dysfunction and a variety of neurodegenerative diseases. Recent investigation has revealed a novel role for autophagy in the context of mental illness, namely in schizophrenia. This article summarizes the phenomenology, genetics, and structural/histopathological brain abnormalities associated with schizophrenia. We review studies that demonstrate for the first time a connection between autophagy malfunction and schizophrenia. Transcriptional profiling in schizophrenia patients uncovered a dysregulation of autophagy-related genes spatially confined to a specific area of the cortex, Brodmann Area 22, which has been previously implicated in the positive symptoms of schizophrenia. We also discuss the role of autophagy activators in schizophrenia and whether they may be useful adjuvants to the traditional antipsychotic medications currently used as the standard of care. In summary, the field has progressed beyond the basic concept that autophagy impairment predisposes to neurodegeneration, to a mechanistic understanding that loss of autophagy can disrupt neuronal cell biology and predispose to mood disorders, psychotic symptoms, and behavioral change. 

scholarly journals α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Lorenzo Di Cesare Mannelli ◽  
Barbara Tenci ◽  
Matteo Zanardelli ◽  
Paola Failli ◽  
Carla Ghelardini
Keyword(s):  
Nicotinic Receptor ◽  
Caspase 3 ◽  
Cell Metabolism ◽  
Strong Increase ◽  
Neuronal Homeostasis ◽  
Relieve Pain ◽  
The Central Nervous System ◽  
Detoxifying Enzyme ◽  
Anti Inflammatory Cytokine

Neuropathies are characterized by a complex response of the central nervous system to injuries. Glial cells are recruited to maintain neuronal homeostasis but dysregulated activation leads to pain signaling amplification and reduces the glial neuroprotective power. Recently, we highlighted the property ofα7 nicotinic-acetylcholine-receptor (nAChR) agonists to relieve pain and induce neuroprotection simultaneously with a strong increase in astrocyte density. Aimed to study the role ofα7 nAChR in the neuron-glia cross-talk, we treated primary rat neurons and astrocytes with the neurotoxic anticancer drug oxaliplatin evaluating the effect of theα7 nAChR agonist PNU-282987 (PNU). Oxaliplatin (1 μM, 48 h) reduced cell viability and increased caspase-3 activity of neuron monocultures without damaging astrocytes. In cocultures, astrocytes were not able to protect neurons by oxaliplatin even if glial cell metabolism was stimulated (pyruvate increase). On the contrary, the coculture incubation with 10 μM PNU improved neuron viability and inhibited apoptosis. In the absence of astrocytes, the protection disappeared. Furthermore, PNU promoted the release of the anti-inflammatory cytokine TGF-β1 and the expression of the glutamate-detoxifying enzyme glutamine synthetase. Theα7 nAChR stimulation protects neurons from oxaliplatin toxicity through an astrocyte-mediated mechanism.α7 nAChR is suggested for recovering the homeostatic role of astrocytes.

scholarly journals The Role of Microglia during West Nile Virus Infection of the Central Nervous System

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 485 ◽  
Author(s):  
Sarah Stonedahl ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
West Nile Virus ◽  
Immune Cells ◽  
Neuronal Cell ◽  
The United States ◽  
Health Concern ◽  
West Nile ◽  
The Central Nervous System

Encephalitis resulting from viral infections is a major cause of hospitalization and death worldwide. West Nile Virus (WNV) is a substantial health concern as it is one of the leading causes of viral encephalitis in the United States today. WNV infiltrates the central nervous system (CNS), where it directly infects neurons and induces neuronal cell death, in part, via activation of caspase 3-mediated apoptosis. WNV infection also induces neuroinflammation characterized by activation of innate immune cells, including microglia and astrocytes, production of inflammatory cytokines, breakdown of the blood-brain barrier, and infiltration of peripheral leukocytes. Microglia are the resident immune cells of the brain and monitor the CNS for signs of injury or pathogens. Following infection with WNV, microglia exhibit a change in morphology consistent with activation and are associated with increased expression of proinflammatory cytokines. Recent research has focused on deciphering the role of microglia during WNV encephalitis. Microglia play a protective role during infections by limiting viral growth and reducing mortality in mice. However, it also appears that activated microglia are triggered by T cells to mediate synaptic elimination at late times during infection, which may contribute to long-term neurological deficits following a neuroinvasive WNV infection. This review will discuss the important role of microglia in the pathogenesis of a neuroinvasive WNV infection. Knowledge of the precise role of microglia during a WNV infection may lead to a greater ability to treat and manage WNV encephalitis.

scholarly journals Ischemic Cerebral Endothelial Cell–Derived Exosomes Promote Axonal Growth

Stroke ◽  
2020 ◽  
Vol 51 (12) ◽  
pp. 3701-3712
Author(s):  
Yi Zhang ◽  
Yi Qin ◽  
Michael Chopp ◽  
Chao Li ◽  
Amy Kemper ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Cell ◽  
Axonal Growth ◽  
Mature Mirnas ◽  
Bioinformatic Analysis ◽  
Axonal Outgrowth ◽  
Ischemic Brain ◽  
Neuronal Homeostasis ◽  
Neuronal Cell Bodies

Background and Purpose: Cerebral endothelial cells (CECs) and axons of neurons interact to maintain vascular and neuronal homeostasis and axonal remodeling in normal and ischemic brain, respectively. However, the role of exosomes in the interaction of CECs and axons in brain under normal conditions and after stroke is unknown. Methods: Exosomes were isolated from CECs of nonischemic rats and is chemic rats (nCEC-exos and isCEC-exos), respectively. A multicompartmental cell culture system was used to separate axons from neuronal cell bodies. Results: Axonal application of nCEC-exos promotes axonal growth of cortical neurons, whereas isCEC-exos further enhance axonal growth than nCEC-exos. Ultrastructural analysis revealed that CEC-exos applied into distal axons were internalized by axons and reached to their parent somata. Bioinformatic analysis revealed that both nCEC-exos and isCEC-exos contain abundant mature miRNAs; however, isCEC-exos exhibit more robust elevation of select miRNAs than nCEC-exos. Mechanistically, axonal application of nCEC-exos and isCEC-exos significantly elevated miRNAs and reduced proteins in distal axons and their parent somata that are involved in inhibiting axonal outgrowth. Blockage of axonal transport suppressed isCEC-exo–altered miRNAs and proteins in somata but not in distal axons. Conclusions: nCEC-exos and isCEC-exos facilitate axonal growth by altering miRNAs and their target protein profiles in recipient neurons.

scholarly journals Autophagy in Neurons

2019 ◽  
Vol 35 (1) ◽  
pp. 477-500 ◽  
Author(s):  
Andrea K.H. Stavoe ◽  
Erika L.F. Holzbaur
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Biology ◽  
Neuronal Development ◽  
Selective Autophagy ◽  
The Core ◽  
Differentiated Cells ◽  
Neuronal Homeostasis ◽  
Core Components ◽  
Cellular Organelles

Autophagy is the major cellular pathway to degrade dysfunctional organelles and protein aggregates. Autophagy is particularly important in neurons, which are terminally differentiated cells that must last the lifetime of the organism. There are both constitutive and stress-induced pathways for autophagy in neurons, which catalyze the turnover of aged or damaged mitochondria, endoplasmic reticulum, other cellular organelles, and aggregated proteins. These pathways are required in neurodevelopment as well as in the maintenance of neuronal homeostasis. Here we review the core components of the pathway for autophagosome biogenesis, as well as the cell biology of bulk and selective autophagy in neurons. Finally, we discuss the role of autophagy in neuronal development, homeostasis, and aging and the links between deficits in autophagy and neurodegeneration.

Insights into multiple sclerosis provided by non-coding RNAs: meeting summary from the symposium ‘Non-coding RNAs in autoimmune disorders of the central nervous system’ on 5 April 2013 in Warsaw, Poland

2014 ◽  
Vol 20 (11) ◽  
pp. 1439-1442 ◽  
Author(s):  
Marcin P Mycko ◽  
Howard L Weiner ◽  
Krzysztof W Selmaj
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Cell Biology ◽  
Potential Role ◽  
Mechanisms Of Action ◽  
Ribonucleic Acids ◽  
The Central Nervous System ◽  
Non Coding Rnas ◽  
Autoimmune Demyelination

More than 80% of the human genome is biochemically active, whereas less than 3% of the genome encodes proteins. The emerging field of non-coding ribonucleic acids (RNAs) that are products of the genome, but do not program proteins, has revolutionized our understanding of cell biology. This was followed by a growing interest in the role of non-coding RNAs in the pathogenesis of human diseases, including multiple sclerosis (MS). In April 2013, a symposium in Warsaw, Poland, was the first meeting entirely dedicated to advances in the understanding of the roles of various subclasses of non-coding RNAs and showcased their involvement in autoimmune demyelination and MS. New mechanisms of action of small non-coding RNAs, as well as the advent of long non-coding RNAs were discussed, including the potential role of non-coding RNAs as MS biomarkers and their use for therapeutic intervention in MS.

scholarly journals Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons

2020 ◽  
Author(s):  
Swetha Gowrishankar ◽  
Lila Lyons ◽  
Nisha Mohd Rafiq ◽  
Agnes Roczniak-Ferguson ◽  
Pietro De Camilli ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cell Biology ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
App Processing ◽  
Induced Pluripotent ◽  
Aβ42 Peptide ◽  
Human Ipsc ◽  
The Relationship

AbstractThe dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer’s disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology.

scholarly journals Extracellular Mitochondria Signals in CNS Disorders

2021 ◽  
Vol 9 ◽  
Author(s):  
Ji-Hyun Park ◽  
Kazuhide Hayakawa
Keyword(s):  
Energy Homeostasis ◽  
Critical Role ◽  
Neuronal Cell Death ◽  
Extracellular Fluid ◽  
Neuronal Cell ◽  
High Energy ◽  
Cns Disorders ◽  
Mitochondrial Transfer ◽  
The Central Nervous System

Mitochondria actively participate in the regulation of cell respiratory mechanisms, metabolic processes, and energy homeostasis in the central nervous system (CNS). Because of the requirement of high energy, neuronal functionality and viability are largely dependent on mitochondrial functionality. In the context of CNS disorders, disruptions of metabolic homeostasis caused by mitochondrial dysfunction lead to neuronal cell death and neuroinflammation. Therefore, restoring mitochondrial function becomes a primary therapeutic target. Recently, accumulating evidence suggests that active mitochondria are secreted into the extracellular fluid and potentially act as non-cell-autonomous signals in CNS pathophysiology. In this mini-review, we overview findings that implicate the presence of cell-free extracellular mitochondria and the critical role of intercellular mitochondrial transfer in various rodent models of CNS disorders. We also discuss isolated mitochondrial allograft as a novel therapeutic intervention for CNS disorders.

Paradoxical Role of 3-Methyladenine in Pyocyanin-Induced Toxicity in 1321N1 Astrocytoma and SH-SY5Y Neuroblastoma Cells

2013 ◽  
Vol 32 (3) ◽  
pp. 209-218 ◽  
Author(s):  
Amelia J. McFarland ◽  
Gary D. Grant ◽  
Anthony V. Perkins ◽  
Cameron Flegg ◽  
Andrew K. Davey ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Inflammatory Responses ◽  
Neuroblastoma Cells ◽  
Astrocytoma Cells ◽  
The Central Nervous System ◽  
Green Fluorescent ◽  
The Impact ◽  
First Time ◽  
1321N1 Astrocytoma

The role of autophagy in pyocyanin (PCN)-induced toxicity in the central nervous system (CNS) remains unclear, with only evidence from our group identifying it as a mechanism underlying toxicity in 1321N1 astrocytoma cells. Therefore, the aim of this study was to further examine the role of autophagy in PCN-induced toxicity in the CNS. To achieve this, we exposed 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells to PCN (0-100 μmol/L) and tested the contribution of autophagy by measuring the impact of the autophagy inhibitor 3-methyladenine (3-MA) using a series of biochemical and molecular markers. Pretreatment of 1321N1 astrocytoma cells with 3-MA (5 mmol/L) decreased the PCN-induced acidic vesicular organelle and autophagosome formation as measured using acridine orange and green fluorescent protein-LC3 -LC3 fluorescence, respectively. Furthermore, 3-MA (5 mmol/L) significantly protected 1321N1 astrocytoma cells against PCN-induced toxicity. In contrast pretreatment with 3-MA (5 mmol/L) increased PCN-induced toxicity in SH-SY5Y neuroblastoma cells. Given the influence of autophagy in inflammatory responses, we investigated whether the observed effects in this study involved inflammatory mediators. The PCN (100 μmol/L) significantly increased the production of interleukin-8 (IL-8), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) in both cell lines. Consistent with its paradoxical role in modulating PCN-induced toxicity, 3-MA (5 mmol/L) significantly reduced the PCN-induced production of IL-8, PGE2, and LTB4 in 1321N1 astrocytoma cells but augmented their production in SH-SY5Y neuroblastoma cells. In conclusion, we show here for the first time the paradoxical role of autophagy in mediating PCN-induced toxicity in 1321N1 astrocytoma and SH-SY5Y neuroblastoma cells and provide novel evidence that these actions may be mediated by effects on IL-8, PGE2, and LTB4 production.

scholarly journals 24-Epibrassinolide, a Phytosterol from the Brassinosteroid Family, Protects Dopaminergic Cells against MPP+-Induced Oxidative Stress and Apoptosis

2011 ◽  
Vol 2011 ◽  
pp. 1-13 ◽  
Author(s):  
Julie Carange ◽  
Fanny Longpré ◽  
Benoit Daoust ◽  
Maria-Grazia Martinoli
Keyword(s):  
Oxidative Stress ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Protein Ratio ◽  
Enzyme Cascade ◽  
Antioxidative Effects ◽  
Neuronal Pc12 Cells ◽  
Induced Apoptosis ◽  
First Time

Oxidative stress and apoptosis are frequently cited to explain neuronal cell damage in various neurodegenerative disorders, such as Parkinson' s disease. Brassinosteroids (BRs) are phytosterols recognized to promote stress tolerance of vegetables via modulation of the antioxidative enzyme cascade. However, their antioxidative effects on mammalian neuronal cells have never been examined so far. We analyzed the ability of 24-epibrassinolide (24-Epi), a natural BR, to protect neuronal PC12 cells from 1-methyl-4-phenylpyridinium- (MPP+-) induced oxidative stress and consequent apoptosis in dopaminergic neurons. Our results demonstrate that 24-Epi reduces the levels of intracellular reactive oxygen species and modulates superoxide dismutase, catalase, and glutathione peroxidase activities. Finally, we determined that the antioxidative properties of 24-Epi lead to the inhibition of MPP+-induced apoptosis by reducing DNA fragmentation as well as the Bax/Bcl-2 protein ratio and cleaved caspase-3. This is the first time that the potent antioxidant and neuroprotective role of 24-Epi has been shown in a mammalian neuronal cell line.

scholarly journals Overlapping roles of JIP3 and JIP4 in promoting axonal transport of lysosomes in human iPSC-derived neurons

2021 ◽  
pp. mbc.E20-06-0382
Author(s):  
Swetha Gowrishankar ◽  
Lila Lyons ◽  
Nisha Mohd Rafiq ◽  
Agnes Roczniak-Ferguson ◽  
Pietro De Camilli ◽  
...  
Keyword(s):  
Axonal Transport ◽  
Cell Biology ◽  
Neuronal Cell ◽  
Induced Pluripotent Stem Cell ◽  
App Processing ◽  
Induced Pluripotent ◽  
Aβ42 Peptide ◽  
Human Ipsc ◽  
The Relationship

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer's disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology. [Media: see text] [Media: see text] [Media: see text] [Media: see text]

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