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Purkinje cells within the cerebellum of patients with multiple sclerosis show signs of apoptosis. Representative human cerebellar sections derived from a patient with multiple sclerosis. Sections are DAB (brown) immunolabelled with cleaved caspase 3 (Asp175) and counterstained with haematoxylin (blue). The oulined area in A is magnified in image B. Active caspase 3-positive cells in A are indicated by red arrows. Scale bar = 300 mm.
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A major conceptual consideration in both endogenous and therapeutic central nervous system repair is how damaged (or senescent) neurons, given their often enormously complex and extensive network of connections, can possibly be replaced. The recent observation of fusion of circulating bone marrow cells with, in particular, cerebellar Purkinje cells...
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... cerebellar inflammation and demyelination in sec- tions derived from patients with multiple sclerosis led us to inves- tigate whether Purkinje cells in the cerebellum were undergoing apoptotic cell death. Using cleaved (active) caspase 3 as an indi- cator of apoptosis, positive Purkinje cells were demonstrable in the cerebellum of these patients (Fig. 3). An almost complete absence of cleaved caspase 3 staining was observed in control sections (data not ...
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Citations
... Cell-cell fusion is a special mechanism that creates polyploid cells without involving cell cycle progression. It is a crucial cellular process in which several mononuclear cells integrate to produce a multinucleated cell [37,38]. Cell fusion is also vital during tissue development and regeneration, as cytotrophoblasts fuse to generate placental syncytiotrophoblasts [39]. ...
Polyploid cells, which contain more than one set of chromosome pairs, are very common in nature. Polyploidy can provide cells with several potential benefits over their diploid counterparts, including an increase in cell size, contributing to organ growth and tissue homeostasis and improving cellular robustness via increased tolerance to genomic stress and apoptotic signals. Here, we focus on why polyploidy in the cell occurs and which stress responses and molecular signals trigger cells to become polyploid. Moreover, we discuss its crucial roles in cell growth and tissue regeneration in the heart, liver and other tissues.
... In addition as GABA promotes autophagic elimination of damaged and virus-infected cells, GABA supplementation may benefit not only COVID-19-affected patients but also those with age-related diseases [5,12]. Cell-cell fusion is a major cause of genome destabilization and generation of aneuploidy, somatic mosaicism, and reactivation of the cell cycle in postmitotic cells [61,[75][76][77][78] (Figure 3). ...
... Neuronal cell-cell fusion occurs physiologically, in normal aging, or pathologically, in various conditions, including viral infections, Alzheimer's disease (AD), multiple sclerosis (MS) radiation exposure, or chemotherapy[76] Neuronal syncytia formation likely accounts for previ ously unexplained phenomena, such as aneuploidy, somatic mosaicism, and neuronal cell cycle re activation, documented in various neuropsychiatric conditions. ...
... Neuronal cell-cell fusion occurs physiologically, in normal aging, or pathologically, in various conditions, including viral infections, Alzheimer's disease (AD), multiple sclerosis (MS), radiation exposure, or chemotherapy[76] Neuronal syncytia formation likely accounts for previously unexplained phenomena, such as aneuploidy, somatic mosaicism, and neuronal cell cycle reactivation, documented in various neuropsychiatric conditions. ...
Infection with SARS-CoV-2, the causative agent of the COVID-19 pandemic, originated in China and quickly spread across the globe. Despite tremendous economic and healthcare devastation, research on this virus has contributed to a better understanding of numerous molecular pathways, including those involving γ-aminobutyric acid (GABA), that will positively impact medical science, including neuropsychiatry, in the post-pandemic era. SARS-CoV-2 primarily enters the host cells through the renin–angiotensin system’s component named angiotensin-converting enzyme-2 (ACE-2). Among its many functions, this protein upregulates GABA, protecting not only the central nervous system but also the endothelia, the pancreas, and the gut microbiota. SARS-CoV-2 binding to ACE-2 usurps the neuronal and non-neuronal GABAergic systems, contributing to the high comorbidity of neuropsychiatric illness with gut dysbiosis and endothelial and metabolic dysfunctions. In this perspective article, we take a closer look at the pathology emerging from the viral hijacking of non-neuronal GABA and summarize potential interventions for restoring these systems.
... The previous histological findings of the present study mimic those changes that occur in patients with MS as described by Kemp et al. [24] who analyzed postmortem cerebellar tissues from patients who had multiple sclerosis and reported an increase in Purkinje cell fusion and heterokaryon formation. Giuliani et al. [25] also reported loss of Purkinje cell layer with demyelination in multiple sclerosis. ...
... The link between the information processing function of neurons and the intricate shapes of their dendritic processes has been the subject of over a century of extensive study [1][2][3]. Morphological features of dendritic arbors, such as length, diameter, and orientation have been related to neuronal functions [4][5][6][7][8][9][10][11][12], while deformations of the dendritic architecture have been associated with diseases and disorders [13][14][15][16][17][18]. Dendritic morphology varies (which was not certified by peer review) is the author/funder. ...
Complex dendritic trees are a distinctive feature of neurons. Alterations to dendritic morphology are associated with developmental, behavioral and neurodegenerative changes. The highly-arborized PVD neuron of C. elegans serves as a model to study dendritic patterning; however, quantitative, objective and automated analyses of PVD morphology are missing. Here, we present a method for neuronal feature extraction, based on deep-learning and fitting algorithms. The extracted neuronal architecture is represented by a database of structural elements for abstracted analysis. We obtain excellent automatic tracing of PVD trees and uncover that dendritic junctions are unevenly distributed. Surprisingly, these junctions are three-way-symmetrical on average, while dendritic processes are arranged orthogonally. We quantify the effect of mutation in git-1 , a regulator of dendritic spine formation, on PVD morphology and discover a localized reduction in junctions. Our findings shed new light on PVD architecture, demonstrating the effectiveness of our objective analyses of dendritic morphology and suggest molecular control mechanisms.
Author Summary
Nerve cells (neurons) collect input signals via branched cellular projections called dendrites. A major aspect of the study of neurons, dating back over a century, involves the characterization of neuronal shapes and of their dendritic processes.
Here, we present an algorithmic approach for detection and classification of the tree-like dendrites of the PVD neuron in C. elegans worms. A key feature of our approach is to represent dendritic trees by a set of fundamental shapes, such as junctions and linear elements. By analyzing this dataset, we discovered several novel structural features. We have found that the junctions connecting branched dendrites have a three-way-symmetry, although the dendrites are arranged in a crosshatch pattern; and that the distribution of junctions varies across distinct sub-classes of the PVD’s dendritic tree. We further quantified subtle morphological effects due to mutation in the git-1 gene, a known regulator of dendritic spines. Our findings suggest molecular mechanisms for dendritic shape regulation and may help direct new avenues of research.
... Whether purkinje cells in the mammalian cerebellum are polyploid has been a matter of considerable debate over the past several decades. (Brodskii et al., 1971;Del Monte, 2006;Kemp et al., 2012;Lapham, 1968;Lapham et al., 1971;Mares et al., 1973;Swartz and Bhatnagar, 1981). Perhaps the most exaggerated examples of polyploidy are from the giant neurons in the terrestrial slug Limax (Yamagishi et al., 2011) and the sea slug Aplysia (Coggeshall et al., 1970) where giant neurons contain >100,000 copies of the diploid genome. ...
Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.
... Whether purkinje cells in the mammalian cerebellum are polyploid has been a matter of considerable debate over the past several decades. (Brodskii et al., 1971;Del Monte, 2006;Kemp et al., 2012;Lapham, 1968;Lapham et al., 1971;Mares et al., 1973;Swartz and Bhatnagar, 1981). Perhaps the most exaggerated examples of polyploidy are from the giant neurons in the terrestrial slug Limax (Yamagishi et al., 2011) and the sea slug Aplysia (Coggeshall et al., 1970) where giant neurons contain >100,000 copies of the diploid genome. ...
Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.
... Whether purkinje cells in the mammalian cerebellum are polyploid has been a matter of considerable debate over the past several decades. (Brodskii et al., 1971;Del Monte, 2006;Kemp et al., 2012;Lapham, 1968;Lapham et al., 1971;Mares et al., 1973;Swartz and Bhatnagar, 1981). Perhaps the most exaggerated examples of polyploidy are from the giant neurons in the terrestrial slug Limax (Yamagishi et al., 2011) and the sea slug Aplysia (Coggeshall et al., 1970) where giant neurons contain >100,000 copies of the diploid genome. ...
Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in adult Drosophila melanogaster brains.
... Whether purkinje cells in the mammalian cerebellum are polyploid has been a matter of considerable debate over the past several decades. [67][68][69][70][71][72][73] . Perhaps the most exaggerated examples of polyploidy are from the giant neurons in the terrestrial slug Limax 74 and the sea slug Aplysia 75 where giant neurons contain >100,000 copies of the diploid genome. ...
Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animals lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adult Drosophila brain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageing Drosophila melanogaster brains.
... Paltsyn and Komissarova [18] suggest that the appearance of the second nucleus is a form of physiological and reparative regeneration of Purkinje cells. Because of the low frequency of Purkinje cell fusion under normal physiological conditions, some authors hypothesize that its role is negligible and fusion is a transient event [8,17]. Magrassi et al. [13] suggest that this cell fusion represents a physiological phenomenon to introduce young nuclei or functional genes in aged or degenerating cells. ...
... In fact, binucleate PC are more frequently demonstrated in old and sick mammals, therefore their occurrence is considered a compensatory mechanism for the age-related or pathogenic loss of Purkinje cells. Inflammation and other pathological conditions in rodents and humans have been shown to promote migration and infiltration of bone marrow-derived stem cells to the site of brain injury [8]. Based on the above, the observed binucleate PC in CoCl 2 -treated suckling mice in our study may be suggested as a sequel of the exposure to the toxic metal. ...
Over the last years, human activities have considerably increased the levels of cobalt (Co) in the environment. Cobalt overexposure is associated with serious health risks, especially in children. The aim of the present study was to examine the effects of perinatal Co treatment on the brain morphology in immature mice. Eighteen-day-old mice were subjected to cobalt chloride (CoCl 2) exposure 2-3 days prior to birth and during the postnatal period. The histopathological studies revealed substantial cerebral and cerebellar damage with features of neuronal necrosis compared to the age-matched healthy controls. In the cerebrum, the neurons, glial cells and the neuropil were affected, as well the Purkinje cells in the cerebellum. The results are indicative of the enhanced susceptibility of the immature brain to the exposure of cobalt. They contribute to the elucidation of the neurotoxic potential of the metal and the related health risks in newborns and infants, especially in regions with cobalt pollution.
... The incidence of BM-derived cells fusing with cerebellar Purkinje cells appears to be very low under normal physiological conditions [22,24,29]. Nevertheless, its biological relevance is suggested by observations that such fusion events in either rodents or humans are substantially increased in number with age [41,42]; or after exposure to cytotoxic agents (for example radiation or chemotherapeutics) [26,42]; or within an inflammatory microenvironment such as that present in multiple sclerosis [22] and in animal models of cerebellar disease [9,10,13,20,21,29]. ...
... The incidence of BM-derived cells fusing with cerebellar Purkinje cells appears to be very low under normal physiological conditions [22,24,29]. Nevertheless, its biological relevance is suggested by observations that such fusion events in either rodents or humans are substantially increased in number with age [41,42]; or after exposure to cytotoxic agents (for example radiation or chemotherapeutics) [26,42]; or within an inflammatory microenvironment such as that present in multiple sclerosis [22] and in animal models of cerebellar disease [9,10,13,20,21,29]. These observations have been taken to suggest that, as Purkinje cells are generated only during early cerebellar development [28], heterotypic cell fusion (fusion between different cell types) acts as a physiological cell rescue mechanism to counter neuronal injury and maintain Purkinje cell function throughout adulthood. ...
... BM-derived cells fusing with Purkinje cells in response to inflammation is of particular importance to cerebellar injury, as cell fusion may be an immune-mediated phenomenon aimed at protecting Purkinje cells against inflammatory or toxic insults [21]. As we report here in mice, inflammatory disease-associated increases in BM-derived cells fusing with Purkinje cells have also been observed in patients who had multiple sclerosis [22]. There is also evidence that underlying levels of cerebellar inflammation influence Purkinje cell fusion and heterokaryon formation in patients with genetic ataxias [24]. ...
Bone marrow-derived cells are known to infiltrate the adult brain and fuse with cerebellar Purkinje cells. Histological observations that such heterotypic cell fusion events are substantially more frequent following cerebellar injury suggest they could have a role in the protection of mature brain neurons. To date, the possibility that cell fusion can preserve or restore the structure and function of adult brain neurons has not been directly addressed; indeed, though frequently suggested, the possibility of benefit has always been rather speculative. Here we report, for the first time, that fusion of a bone marrow-derived cell with a neuron in vivo, in the mature brain, results in the formation of a spontaneously firing neuron. Notably, we also provide evidence supporting the concept that heterotypic cell fusion acts as a biological mechanism to repair pathological changes in Purkinje cell structure and electrophysiology. We induced chronic central nervous system inflammation in chimeric mice expressing bone marrow cells tagged with enhanced green fluorescent protein. Subsequent in-depth histological analysis revealed significant Purkinje cell injury. In addition, there was an increased incidence of cell fusion between bone marrow-derived cells and Purkinje cells, revealed as enhanced green fluorescent protein-expressing binucleate heterokaryons. These fused cells resembled healthy Purkinje cells in their morphology, soma size, ability to synthesize the neurotransmitter gamma-aminobutyric acid, and synaptic innervation from neighbouring cells. Extracellular recording of spontaneous firing ex vivo revealed a shift in the predominant mode of firing of non-fused Purkinje cells in the context of cerebellar inflammation. By contrast, the firing patterns of fused Purkinje cells were the same as in healthy control cerebellum, indicating that fusion of bone marrow-derived cells with Purkinje cells mitigated the effects of cell injury on electrical activity. Together, our histological and electrophysiological results provide novel fundamental insights into physiological processes by which nerve cells are protected in adult life.
Electronic supplementary material
The online version of this article (10.1007/s00401-018-1833-z) contains supplementary material, which is available to authorized users.
