scholarly journals Axonal Transport Enables Neuron-to-Neuron Propagation of Human Coronavirus OC43

2018 ◽  
Vol 92 (17) ◽  
Author(s):  
Mathieu Dubé ◽  
Alain Le Coupanec ◽  
Alan H. M. Wong ◽  
James M. Rini ◽  
Marc Desforges ◽  
...  
Keyword(s):  
Cell Culture ◽  
Brain Stem ◽  
Axonal Transport ◽  
Neurological Diseases ◽  
Neuronal Cell ◽  
Therapeutic Interventions ◽  
Respiratory Pathogens ◽  
Upper Respiratory Tract ◽  
Human Coronaviruses ◽  
The Brain

ABSTRACTHuman coronaviruses (HCoVs) are recognized respiratory pathogens for which accumulating evidence indicates that in vulnerable patients the infection can cause more severe pathologies. HCoVs are not always confined to the upper respiratory tract and can invade the central nervous system (CNS) under still unclear circumstances. HCoV-induced neuropathologies in humans are difficult to diagnose early enough to allow therapeutic interventions. Making use of our already described animal model of HCoV neuropathogenesis, we describe the route of neuropropagation from the nasal cavity to the olfactory bulb and piriform cortex and then the brain stem. We identified neuron-to-neuron propagation as one underlying mode of virus spreading in cell culture. Our data demonstrate that both passive diffusion of released viral particles and axonal transport are valid propagation strategies used by the virus. We describe for the first time the presence along axons of viral platforms whose static dynamism is reminiscent of viral assembly sites. We further reveal that HCoV OC43 modes of propagation can be modulated by selected HCoV OC43 proteins and axonal transport. Our work, therefore, identifies processes that may govern the severity and nature of HCoV OC43 neuropathogenesis and will make possible the development of therapeutic strategies to prevent occurrences.IMPORTANCECoronaviruses may invade the CNS, disseminate, and participate in the induction of neurological diseases. Their neuropathogenicity is being increasingly recognized in humans, and the presence and persistence of human coronaviruses (HCoV) in human brains have been proposed to cause long-term sequelae. Using our mouse model relying on natural susceptibility to HCoV OC43 and neuronal cell cultures, we have defined the most relevant path taken by HCoV OC43 to access and spread to and within the CNS toward the brain stem and spinal cord and studied in cell culture the underlying modes of intercellular propagation to better understand its neuropathogenesis. Our data suggest that axonal transport governs HCoV OC43 egress in the CNS, leading to the exacerbation of neuropathogenesis. Exploiting knowledge on neuroinvasion and dissemination will enhance our ability to control viral infection within the CNS, as it will shed light on underlying mechanisms of neuropathogenesis and uncover potential druggable molecular virus-host interfaces.

Form and Function in Cells of the Brain

The Neuron ◽  
2015 ◽  
pp. 23-38
Author(s):  
Irwin B. Levitan ◽  
Leonard K. Kaczmarek
Keyword(s):  
Axonal Transport ◽  
Molecular Motors ◽  
Critical Role ◽  
Neuronal Cell ◽  
Cell Types ◽  
Neuronal Cell Body ◽  
Long Distance ◽  
Form And Function ◽  
And Function ◽  
The Brain

This chapter examines unique mechanisms that the neuron has evolved to establish and maintain the form required for its specialized signaling functions. Unlike some other organs, the brain contains a variety of cell types including several classes of glial cells, which play a critical role in the formation of the myelin sheath around axons and may be involved in immune responses, synaptic transmission, and long-distance calcium signaling in the brain. Neurons share many features in common with other cells (including glia), but they are distinguished by their highly asymmetrical shapes. The neuronal cytoskeleton is essential for establishing this cell shape during development and for maintaining it in adulthood. The process of axonal transport moves vesicles and other organelles to regions remote from the neuronal cell body. Proteins such as kinesin and dynein, called molecular motors, make use of the energy released by hydrolysis of ATP to drive axonal transport.

Early Defects of GABAergic Synapses in the Brain Stem of a MeCP2 Mouse Model of Rett Syndrome

2008 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
L. Medrihan ◽  
E. Tantalaki ◽  
G. Aramuni ◽  
V. Sargsyan ◽  
I. Dudanova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Brain Stem ◽  
Rett Syndrome ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Ventrolateral Medulla ◽  
Diagnostic Tools ◽  
The Brain

Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic γ-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABAA-receptor subunits α2 and α4. Our data indicate that in the MeCP2 −/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

scholarly journals Cell type-specific biotin labeling in vivo resolves regional neuronal proteomic differences in mouse brain

2021 ◽  
Author(s):  
Sruti Rayaprolu ◽  
Sara Bitarafan ◽  
Ranjita Betarbet ◽  
Sydney N Sunna ◽  
Lihong Cheng ◽  
...  
Keyword(s):  
Mouse Brain ◽  
Neurological Diseases ◽  
Neuronal Cell ◽  
Cell Types ◽  
Proteomic Profiling ◽  
Cell Type ◽  
Specific Expression ◽  
Cell Type Specific ◽  
The Brain

Isolation and proteomic profiling of brain cell types, particularly neurons, pose several technical challenges which limit our ability to resolve distinct cellular phenotypes in neurological diseases. Therefore, we generated a novel mouse line that enables cell type-specific expression of a biotin ligase, TurboID, via Cre-lox strategy for in vivo proximity-dependent biotinylation of proteins. Using adenoviral-based and transgenic approaches, we show striking protein biotinylation in neuronal cell bodies and axons throughout the mouse brain. We quantified more than 2,000 neuron-derived proteins following enrichment that mapped to numerous subcellular compartments. Synaptic, transmembrane transporters, ion channel subunits, and disease-relevant druggable targets were among the most significantly enriched proteins. Remarkably, we resolved brain region-specific proteomic profiles of Camk2a neurons with distinct functional molecular signatures and disease associations that may underlie regional neuronal vulnerability. Leveraging the neuronal specificity of this in vivo biotinylation strategy, we used an antibody-based approach to uncover regionally unique patterns of neuron-derived signaling phospho-proteins and cytokines, particularly in the cortex and cerebellum. Our work provides a proteomic framework to investigate cell type-specific mechanisms driving physiological and pathological states of the brain as well as complex tissues beyond the brain.

scholarly journals The location of cardiac vagal preganglionic neurones in the brain stem of the dogfish Scyliorhinus canicula

1985 ◽  
Vol 117 (1) ◽  
pp. 449-458 ◽  
Author(s):  
D. J. Barrett ◽  
E. W. Taylor
Keyword(s):  
Horseradish Peroxidase ◽  
Brain Stem ◽  
Axonal Transport ◽  
Middle Group ◽  
Scyliorhinus Canicula ◽  
Concentrated Solution ◽  
The Brain

The locations, within the brain stem, of vagal efferent preganglionic neurones with axons in the two pairs of cardiac vagal rami of the dogfish have been defined by the retrograde intra-axonal transport of horseradish peroxidase (HRP). HRP was applied to the cardiac rami in one of two ways: either as crystals placed on the cut central end of the nerve or as a dried concentrated solution administered into the nerve on the tip of a fine pin. No difference was observed in the number of labelled cell bodies identified using either method. Labelled branchial cardiac vagal motoneurones were found ipsilaterally in the medial division of the vagal motor column, in the lateral division of the vagal motor column, and scattered between these two locations. In contrast, visceral cardiac vagal motoneurones were confined to the ipsilateral medial division of the vagal motor column. We suggest that the dual location of cell bodies supplying axons to the branchial cardiac branch of the vagus may represent a separation of function with respect to the two types of activity conducted by this nerve. Cardiac efferent fibres are confined in their exit from the brain to a middle group of vagal rootlets. This corresponds to the topographical representation of cardiac efferent somata within the extent of the vagal motor column.

scholarly journals Pivotal Role of Receptor-Interacting Protein Kinase 1 and Mixed Lineage Kinase Domain-Like in Neuronal Cell Death Induced by the Human Neuroinvasive Coronavirus OC43

2016 ◽  
Vol 91 (1) ◽  
Author(s):  
Mathieu Meessen-Pinard ◽  
Alain Le Coupanec ◽  
Marc Desforges ◽  
Pierre J. Talbot
Keyword(s):  
Cell Death ◽  
Significant Role ◽  
Neurological Diseases ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Pivotal Role ◽  
Death Process ◽  
Potential Implication ◽  
Human Coronaviruses

ABSTRACT Human coronaviruses (HCoV) are respiratory pathogens with neuroinvasive, neurotropic, and neurovirulent properties, highlighting the importance of studying the potential implication of these viruses in neurological diseases. The OC43 strain (HCoV-OC43) was reported to induce neuronal cell death, which may participate in neuropathogenesis. Here, we show that HCoV-OC43 harboring two point mutations in the spike glycoprotein (rOC/Us183–241) was more neurovirulent than the wild-type HCoV-OC43 (rOC/ATCC) in mice and induced more cell death in murine and human neuronal cells. To evaluate the role of regulated cell death (RCD) in HCoV-OC43-mediated neural pathogenesis, we determined if knockdown of Bax, a key regulator of apoptosis, or RIP1, a key regulator of necroptosis, altered the percentage of neuronal cell death following HCoV-OC43 infection. We found that Bax-dependent apoptosis did not play a significant role in RCD following infection, as inhibition of Bax expression mediated by RNA interference did not confer cellular protection against the cell death process. On the other hand, we demonstrated that RIP1 and MLKL were involved in neuronal cell death, as RIP1 knockdown and chemical inhibition of MLKL significantly increased cell survival after infection. Taken together, these results indicate that RIP1 and MLKL contribute to necroptotic cell death after HCoV-OC43 infection to limit viral replication. However, this RCD could lead to neuronal loss in the mouse CNS and accentuate the neuroinflammation process, reflecting the severity of neuropathogenesis. IMPORTANCE Because they are naturally neuroinvasive and neurotropic, human coronaviruses are suspected to participate in the development of neurological diseases. Given that the strain OC43 is neurovirulent in mice and induces neuronal cell death, we explored the neuronal response to infection by characterizing the activation of RCD. Our results revealed that classical apoptosis associated with the Bax protein does not play a significant role in HCoV-OC43-induced neuronal cell death and that RIP1 and MLKL, two cellular proteins usually associated with necroptosis (an RCD back-up system when apoptosis is not adequately induced), both play a pivotal role in the process. As necroptosis disrupts cellular membranes and allows the release of damage-associated molecular patterns (DAMP) and possibly induces the production of proinflammatory cytokines, it may represent a proinflammatory cell death mechanism that contributes to excessive neuroinflammation and neurodegeneration and eventually to neurological disorders after a coronavirus infection.

scholarly journals Axonal Transport Of An Insulin-Like Peptide Mrna Promotes Stress Recovery In C. Elegans

2019 ◽  
Author(s):  
Rashmi Chandra ◽  
Lisa Li ◽  
Zahabiya Husain ◽  
Shashwat Mishra ◽  
Joy Alcedo
Keyword(s):  
Insulin Receptor ◽  
Axonal Transport ◽  
Neurological Diseases ◽  
Rapid Recovery ◽  
Stress Recovery ◽  
C Elegans ◽  
Golgi Bodies ◽  
The Brain

ABSTRACTAberrations in insulin or insulin-like peptide (ILP) signaling in the brain causes many neurological diseases. Here we report that mRNAs of specific ILPs are surprisingly mobilized to the axons of C. elegans during stress. Transport of the ILP ins-6 mRNA to axons facilitates recovery from stress, whereas loss of axonal mRNA delays recovery. In addition, the axonal traffic of ins-6 mRNA is regulated by at least two opposing signals: one that depends on the insulin receptor DAF-2 and a kinesin-2 motor; and a second signal that is independent of DAF-2, but involves a kinesin-3 motor. While Golgi bodies that package nascent peptides, like ILPs, have not been previously found in C. elegans axons, we show that axons of stressed C. elegans have increased Golgi ready to package peptides for secretion. Thus, our findings present a mechanism that facilitates an animal’s rapid recovery from stress through axonal ILP mRNA mobilization.

scholarly journals Neuroinvasion by Human Respiratory Coronaviruses

2000 ◽  
Vol 74 (19) ◽  
pp. 8913-8921 ◽  
Author(s):  
Nathalie Arbour ◽  
Robert Day ◽  
Jia Newcombe ◽  
Pierre J. Talbot
Keyword(s):  
Neurological Diseases ◽  
Point Mutations ◽  
Brain Parenchyma ◽  
N Gene ◽  
Respiratory Pathogens ◽  
Reverse Transcription Pcr ◽  
Human Coronaviruses ◽  
Human Brains

ABSTRACT Human coronaviruses (HCoV) cause common colds but can also infect neural cell cultures. To provide definitive experimental evidence for the neurotropism and neuroinvasion of HCoV and its possible association with multiple sclerosis (MS), we have performed an extensive search and characterization of HCoV RNA in a large panel of human brain autopsy samples. Very stringent reverse transcription-PCR with two primer pairs for both viral strains (229E and OC43), combined with Southern hybridization, was performed on samples from 90 coded donors with various neurological diseases (39 with MS and 26 with other neurological diseases) or normal controls (25 patients). We report that 44% (40 of 90) of donors were positive for 229E and that 23% (21 of 90) were positive for OC43. A statistically significant higher prevalence of OC43 in MS patients (35.9%; 14 of 39) than in controls (13.7%; 7 of 51) was observed. Sequencing of nucleocapsid protein (N) gene amplicons revealed point mutations in OC43, some consistently found in three MS patient brains and one normal control but never observed in laboratory viruses. In situ hybridization confirmed the presence of viral RNA in brain parenchyma, outside blood vessels. The presence of HCoV in human brains is consistent with neuroinvasion by these respiratory pathogens. Further studies are needed to distinguish between opportunistic and disease-associated viral presence in human brains.

scholarly journals The role of olfactory transport in the penetration of manganese oxide nanoparticles from blood into the brain

2019 ◽  
Vol 23 (4) ◽  
pp. 482-488
Author(s):  
A. V. Romashchenko ◽  
M. B. Sharapova ◽  
К. N. Morozova ◽  
E. V. Kiseleva ◽  
K. E. Kuper ◽  
...  
Keyword(s):  
Nasal Cavity ◽  
Manganese Oxide ◽  
Axonal Transport ◽  
Neurological Diseases ◽  
Specific Inhibitor ◽  
Practical Interest ◽  
Submicron Particles ◽  
Neurotropic Viruses ◽  
The Central Nervous System ◽  
The Brain

There is no doubt that various nanoparticles (NPs) can enter the brain from the nasal cavity. It is assumed that NPs can penetrate from blood into the central nervous system (CNS) only by breaking the blood–brain barrier (BBB). The accumulation of NPs in CNS can provoke many neurological diseases; therefore, the understanding of its mechanisms is of both academic and practical interest. Although hitting from the surface of the lungs into the bloodstream, NPs can accumulate in various mucous membranes, including the nasal mucosa. Thus, we cannot rule out the ability of NPs to be transported from the bloodstream to the brain through the olfactory uptake. To test this hypothesis, we used paramagnetic NPs of manganese oxide (Mn3O4-NPs), whose accumulation patterns in the mouse brain were recorded using T1-weighted magnetic resonance imaging. The effect of intranasal application of endocytosis and axonal transport inhibitors on the brain accumulation patterns of intranasally or intravenously injected Mn3O4-NPs was evaluated. A comparative analysis of the results showed that the transport of Mn3O4-NPs from the nasal cavity to the brain is more efficient than their local permeation through BBB into CNS from the bloodstream, for example with the accumulation of Mn3O4NPs in the dentate gyrus of the hippocampus, and through the capture and transport of NPs from the blood by olfactory epithelium cells. Also, experiments with the administration of chlorpromazine, a specific inhibitor of clathrin-dependent endocytosis, and methyl-β-cyclodextrin, inhibitor of the lipid rafts involved in the capture of substances by endothelium cells, showed differences in the mechanisms of NP uptake from the nasal cavity and from the bloodstream. In this study, we show a significant contribution of axonal transport to NP accumulation patterns in the brain, both from the nasal cavity and from the vascular bed. This explains the accumulation of different sorts of submicron particles (neurotropic viruses, insoluble xenobiotics, etc.), unable to pass BBB, in the brain. The results will add to the understanding of the pathogenesis of various neurodegenerative diseases and help studying the side effects of therapeutics administered intravenously.

scholarly journals Once the Light Touch to the Brain: Cytotoxic Effects of Low-Dose Gamma-Ray, Laser Light, and Visible Light on Rat Neuronal Cell Culture

2016 ◽  
Vol 48 (2) ◽  
pp. 76-83
Author(s):  
Murteza Cakir ◽  
Abdullah Colak ◽  
Cagatay Calikoglu ◽  
Numan Taspinar ◽  
Mustafa Erdem Sagsoz ◽  
...  
Keyword(s):  
Cell Culture ◽  
Visible Light ◽  
Low Dose ◽  
Gamma Ray ◽  
Laser Light ◽  
Neuronal Cell ◽  
Light Touch ◽  
Cytotoxic Effects ◽  
Neuronal Cell Culture ◽  
The Brain
Sign in / Sign up

Export Citation Format

Share Document