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This study was aimed at evaluating the role of increased iron accumulation in oligodendrocytes and its role in their apoptosis in the periventricular white matter damage (PWMD) following a hypoxic injury to the neonatal brain. In response to hypoxia, in the PWM, there was increased expression of proteins involved in iron acquisition, such as iron regulatory proteins (IRP1, IRP2) and transferrin receptor in oligodendrocytes. Consistent with this, following a hypoxic exposure, there was increased accumulation of iron in primary cultured oligodendrocytes. The increased concentration of iron within hypoxic oligodendrocytes was found to elicit ryanodine receptor (RyR) expression, and the expression of endoplasmic reticulum (ER) stress markers such as binding-immunoglobulin protein (BiP) and inositol-requiring enzyme (IRE)-1α. Associated with ER stress, there was reduced adenosine triphosphate (ATP) levels within hypoxic oligodendrocytes. However, treatment with deferoxamine reduced the increased expression of RyR, BiP, and IRE-1α and increased ATP levels in hypoxic oligodendrocytes. Parallel to ER stress there was enhanced reactive oxygen species production within mitochondria of hypoxic oligodendrocytes, which was attenuated when these cells were treated with deferoxamine. At the ultrastructural level, hypoxic oligodendrocytes frequently showed dilated ER and disrupted mitochondria, which became less evident in those treated with deferoxamine. Associated with these subcellular changes, the apoptosis of hypoxic oligodendrocytes was evident with an increase in p53 and caspase-3 expression, which was attenuated when these cells were treated with deferoxamine. Thus, the present study emphasizes that the excess iron accumulated within oligodendrocytes in hypoxic PWM could result in their death by eliciting ER stress and mitochondrial disruption. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI.

Background Demyelination is one of the most important pathological factors of spinal cord injury. Oligodendrocyte apoptosis is involved in triggering demyelination. However, fewer reports on pathological changes and mechanism of demyelination have been presented from compressed spinal cord injury ( CSCI). The relative effect of oligodendrocyte apoptosis on CSCI-induced demyelination and the mechanism of apoptosis remain unclear. Aims In this study, a custom-designed model of CSCI was used to determine whether or not demyelination and oligodendrocyte apoptosis occur after CSCI. The pathological changes in axonal myelinated fibers were investigated by osmic acid staining and transmission electron microscopy. Myelin basic protein (MBP), which is used in myelin formation in the central nervous system, was detected by immunofluorescence and Western blot assays. Oligodendrocyte apoptosis was revealed by in situ terminal-deoxytransferase-mediated dUTP nick-end labeling. To analyze the mechanism of oligodendrocyte apoptosis, we detected caspase-12 [a representative of endoplasmic reticulum (ER) stress], cytochrome c (an apoptotic factor and hallmark of mitochondria), and inhibitor of DNA binding 2 (Id2, an oligodendrocyte lineage gene) by immunofluorescence and Western blot assays. Results The custom-designed model of CSCI was successfully established. The rats were spastic, paralyzed, and incontinent. The Basso, Beattie, and Bresnahan ( BBB) locomotor rating scale scores were decreased as time passed. The compressed spinal cord slices were ischemic. Myelin sheaths became swollen and degenerative; these sheaths were broken down as time passed after CSCI. MBP expression was downregulated after CSCI and consistent with the degree of demyelination. Oligodendrocyte apoptosis occurred at 1 day after CSCI and increased as caspase-12 expression was enhanced and cytochrome c was released. Id2 was distributed widely in the white matter. Id2 expression increased with time after CSCI. Conclusion Demyelination occurred after CSCI and might be partly caused by oligodendrocyte apoptosis, which was positively correlated with ER-mitochondria interactions and enhanced Id2 expression after CSCI in rats. [ABSTRACT FROM AUTHOR]

Oligodendrocyte loss and demyelination are major pathological hallmarks of multiple sclerosis. In pattern III lesions, inflammation is minor in the early stages, and oligodendrocyte apoptosis prevails, which appears to be mediated at least in part through mitochondrial injury. Here, we demonstrate poly(ADP-ribose) polymerase activation and apoptosis inducing factor nuclear translocation within apoptotic oligodendrocytes in such multiple sclerosis lesions. The same morphological and molecular pathology was observed in an experimental model of primary demyelination, induced by the mitochondrial toxin cuprizone. Inhibition of poly(ADP-ribose) polymerase in this model attenuated oligodendrocyte depletion and decreased demyelination. Poly(ADP-ribose) polymerase inhibition suppressed c-Jun N-terminal kinase and p38 mitogen-activated protein kinase phosphorylation, increased the activation of the cytoprotective phosphatidylinositol-3 kinase-Akt pathway and prevented caspase-independent apoptosis inducing factor-mediated apoptosis. Our data indicate that poly(ADP-ribose) polymerase activation plays a crucial role in the pathogenesis of pattern III multiple sclerosis lesions. Since poly(ADP-ribose) polymerase inhibition was also effective in the inflammatory model of multiple sclerosis, it may target all subtypes of multiple sclerosis, either by preventing oligodendrocyte death or attenuating inflammation. [ABSTRACT FROM PUBLISHER]

There is increasing evidence that proteins normally involved in the cell cycle play a role in the regulation of neuronal apoptotic death following various insults. However, it is not clear if the same mechanisms regulate cell death of oligodendrocytes as well. In this study, we investigated the mechanism of ceramide-induced apoptosis in primary rat oligodendrocytes. We show that ceramide treatment initiates a cascade of biochemical events involving cell cycle regulatory proteins. Although at the time of induction of cell death the oligodendrocytes are postmitotic, activation of c-myc and translocation of Cdc25A into the nucleus can be demonstrated. Of particular interest are the findings of the up-regulation of PCNA and down-regulation of p21WAF1/CIP1 protein, an inhibitor of cell-cycle progression. The current results show that activation of regulatory cell-cycle proteins at the oligodendrocytes G1-S checkpoint may constitute a crucial step of the death pathway of oligodendrocytes. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a major cause of disability, and at present, there is no universally accepted treatment. The functional decline following SCI is contributed to both direct mechanical injury and secondary pathophysiological mechanisms that are induced by the initial trauma. These mechanisms initially involve widespread haemorrhage at the site of injury and necrosis of central nervous system (CNS) cellular components. At later stages of injury, the cord is observed to display reactive gliosis. The actions of astrocytes as well as numerous other cells in this response create an environment that is highly nonpermissive to axonal regrowth. Also manifesting important effects is the immune system. The early recruitment of neutrophils and at later stages, macrophages to the site of insult cause exacerbation of injury. However, at more chronic stages, macrophages and recruited T helper cells may potentially be helpful by providing trophic support for neuronal and non-neuronal components of the injured CNS. Within this sea of injurious mechanisms, the oligodendrocytes appear to be highly vulnerable. At chronic stages of SCI, a large number of oligodendrocytes undergo apoptosis at sites that are distant to the vicinity of primary injury. This leads to denudement of axons and deterioration of their conductive abilities, which adds significantly to functional decline. By indulging into the molecular mechanisms that cause oligodendrocyte apoptosis and identifying potential targets for therapeutic intervention, the prevention of this apoptotic wave will be of tremendous value to individuals living with SCI. [Copyright &y& Elsevier]

This study examined the roles of microglia and monocytes in myelin destruction in patients with early multiple sclerosis (MS). Twenty-two cases were studied; the clinical duration was <9 weeks in 10 cases. Twenty myeloid cell subtypes or categories were identified including 2 cell types not known previously to occur in demyelinating diseases. Commencing myelin breakdown in plaques and in perivascular and subpial tissues occurred in the immediate presence of infiltrating monocytes and was effected by a homogeneous population of IgG-positive Fc receptor-bearing early phagocytes interacting with abnormal myelin. Oligodendrocyte apoptosis was observed in intact myelinated tissue bordering areas of active demyelination. Capillaries in the cerebral cortex plugged by large numbers of monocytes were common in acute cases of MS and in a patient with a neuromyelitis optica variant and extreme systemic recruitment of monocytes. In an MS patient with progressive disease, microglial nodules centered on MHC-II-positive capillaries plugged by monocytes were present in the cerebral cortex. This constitutes a new gray matter lesion in MS., (© 2021 American Association of Neuropathologists, Inc.)

Neuregulins are a family of genes involved in key aspects of neural biology. Neuregulins 1, 2 and 3 (NRG1, NRG2 and NRG3) are expressed in the mammalian nervous system. It is well established that NRG1, with fifteen different splicing forms, is central for brain development and function. However, the biological relevance of NRG2 and NRG3 remains elusive. Here, we report the identification of a new isoform of NRG3 that is specifically expressed in the human embryonic central nervous system. Sequence alignment with the human genome suggests that this transcript is produced by alternative promoter usage. The encoded polypeptide is a type-I-glycosylated plasma membrane protein, which is shed into the extracellular space where it activates erbB4, a pivotal receptor for brain development. In addition, we show that the protein has a signal sequence that is cleaved after membrane insertion. Proteasome inhibition with Lactacystin enhances the expression of the protein, whereas impairment of ubiquitylation in the conditional mutant cell line ts20 protects the protein from degradation. These observations imply that the ubiquitin/proteasome pathway regulates biogenesis of the protein. We also show that recombinant neuregulin 3 acts as an oligodendrocyte survival factor by activating the phosphoinositide 3-kinase signalling pathway. Therefore, we report a new post-translationally regulated isoform of neuregulin 3 expressed in the developing human central nervous system with a role in oligodendrocyte survival. [ABSTRACT FROM AUTHOR]