Multinucleated Arginine-Vasopressin Neurons in the Human Supraoptic Nucleus: A Hallmark of Pulmonary Pathology

Ishunina, Tatjana A.; Unmehopa, Unga A.; Dolzhikov, A. A.; Swaab, Dick F.

doi:10.1159/000054600

Cited by 8 publications

(4 citation statements)

References 29 publications

(37 reference statements)

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“…Recent studies in Caenorhabditis elegans (C. elegans) reported fusogen-mediated neuron-neuron and neuron-glia mergers, suggesting that syncytia formation may drive neurocognition ( Alexander et al., 2014 ; Giordano-Santini et al., 2020 ). Moreover, multinucleated neurons in the supraoptic nucleus were demonstrated in patients with pneumonia, a disease often associated with respiratory viruses, likely implicating virus-usurped host fusogens in this pathology ( Ishunina et al., 2000 ). Fusion of bone marrow cells with Purkinje neurons have been documented by both clinical and preclinical studies, indicating that peripheral and brain cells can merge ( Alvarez-Dolado et al., 2003 ).…”

Section: Introductionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Section: Introductionmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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“…No neuronal swelling or neuronolysis was observed in the neuroendocrine nuclei of the cases studied. Multinucleated AVP neurones, which have been associated with hypoxia in the adult , were not found.…”

Section: Discussionmentioning

confidence: 79%

The Human Neurosecretory Neurones Under Perinatal Hypoxia: A Quantitative Immunohistochemical Study of the Supraoptic Nucleus in Autopsy Material

Pagida

Konstantinidou

Malidelis

et al. 2013

J Neuroendocrinology

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In the rat, experimental manipulations that cause activation of the magnocellular neurosecretory neurones result in the synthesis, in addition to vasopressin (AVP) and oxytocin (OXY), of other neurotransmitters or peptides, including tyrosine hydroxylase (TH), the first and rate limiting enzyme for catecholamine biosynthesis. In the human neonate, our previous study showed that TH was selectively increased in AVP neurones of subjects that died from prolonged perinatal hypoxia. The purpose of the present study was to quantitatively investigate the expression of TH, AVP, OXY and neurophysin in magnocellular neurones of the human neonate in relation to the severity/duration of perinatal hypoxia, as estimated by neuropathological criteria. Autopsy was performed after obtaining parental written consent for diagnostic and research purposes. The intensity of the immunohistochemical reactions and the cellular/nuclear size were measured in the dorsolateral supraoptic nucleus using a computerised image analysis system. We showed that prolonged perinatal hypoxia resulted in the activation of the magnocellular neuroendocrine neurones of the human neonate, as indicated by their increased neuronal and nuclear size. OXY neurones appeared larger than the AVP ones at birth, possibly indicating an active role of foetal OXY during labour or even earlier. The gradual increase in the duration of the insult resulted in the reduction of intracellular AVP content, in parallel with a dramatic increase in the expression of TH, indicating a functional interaction of these peptides under neuronal activation. Ιsolated evidence in our series, obtained from an infant of a diabetic mother, raises the probability that in the case of hyperglycaemia the above pathogenetic mechanisms are diversified.

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“…tients with pneumonia, suggesting that fusogenic viruses can access the brain [94]. Moreover, neuronal syncytia were demonstrated in both normal and pathological aging, suggesting that aneuploidy and polyploidy could be more common in the human brain than currently believed [95,96].…”

Section: Fusion Of Postmitotic Cells: Heart and Brain Syncytiamentioning

confidence: 99%

“…For example, the fusion of Purkinje neurons with bone marrow cells was demonstrated in both humans and rodents, suggesting that neurons can fuse not only with each other but also with somatic cells [ 29 , 93 ]. In addition, multinucleated neurons in the supraoptic nucleus were found in patients with pneumonia, suggesting that fusogenic viruses can access the brain [ 94 ]. Moreover, neuronal syncytia were demonstrated in both normal and pathological aging, suggesting that aneuploidy and polyploidy could be more common in the human brain than currently believed [ 95 , 96 ].…”

Section: Fusion Of Postmitotic Cells: Heart and Brain Syncytiamentioning

confidence: 99%

Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

Sfera

Rahman

Campo

et al. 2023

IJMS

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Long COVID, also called post-acute sequelae of SARS-CoV-2, is characterized by a multitude of lingering symptoms, including impaired cognition, that can last for many months. This symptom, often called “brain fog”, affects the life quality of numerous individuals, increasing medical complications as well as healthcare expenditures. The etiopathogenesis of SARS-CoV-2-induced cognitive deficit is unclear, but the most likely cause is chronic inflammation maintained by a viral remnant thriving in select body reservoirs. These viral sanctuaries are likely comprised of fused, senescent cells, including microglia and astrocytes, that the pathogen can convert into neurotoxic phenotypes. Moreover, as the enteric nervous system contains neurons and glia, the virus likely lingers in the gastrointestinal tract as well, accounting for the intestinal symptoms of long COVID. Fusogens are proteins that can overcome the repulsive forces between cell membranes, allowing the virus to coalesce with host cells and enter the cytoplasm. In the intracellular compartment, the pathogen hijacks the actin cytoskeleton, fusing host cells with each other and engendering pathological syncytia. Cell–cell fusion enables the virus to infect the healthy neighboring cells. We surmise that syncytia formation drives cognitive impairment by facilitating the “seeding” of hyperphosphorylated Tau, documented in COVID-19. In our previous work, we hypothesized that the SARS-CoV-2 virus induces premature endothelial senescence, increasing the permeability of the intestinal and blood–brain barrier. This enables the migration of gastrointestinal tract microbes and/or their components into the host circulation, eventually reaching the brain where they may induce cognitive dysfunction. For example, translocated lipopolysaccharides or microbial DNA can induce Tau hyperphosphorylation, likely accounting for memory problems. In this perspective article, we examine the pathogenetic mechanisms and potential biomarkers of long COVID, including microbial cell-free DNA, interleukin 22, and phosphorylated Tau, as well as the beneficial effect of transcutaneous vagal nerve stimulation.

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Multinucleated Arginine-Vasopressin Neurons in the Human Supraoptic Nucleus: A Hallmark of Pulmonary Pathology

Cited by 8 publications

References 29 publications

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

The Human Neurosecretory Neurones Under Perinatal Hypoxia: A Quantitative Immunohistochemical Study of the Supraoptic Nucleus in Autopsy Material

Long COVID as a Tauopathy: Of “Brain Fog” and “Fusogen Storms”

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