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Cold Spring Harbor Perspectives in... Mar 2018Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), which gives rise to focal lesions in the gray and white matter and to diffuse neurodegeneration in the entire brain. In this review, the spectrum of MS lesions and their relation to the inflammatory process is described. Pathology suggests that inflammation drives tissue injury at all stages of the disease. Focal inflammatory infiltrates in the meninges and the perivascular spaces appear to produce soluble factors, which induce demyelination or neurodegeneration either directly or indirectly through microglia activation. The nature of these soluble factors, which are responsible for demyelinating activity in sera and cerebrospinal fluid of the patients, is currently undefined. Demyelination and neurodegeneration is finally accomplished by oxidative injury and mitochondrial damage leading to a state of "virtual hypoxia."
Topics: Brain; Demyelinating Diseases; Disease Progression; Humans; Inflammation; Multiple Sclerosis; Nerve Degeneration
PubMed: 29358320
DOI: 10.1101/cshperspect.a028936 -
Neurologia 2020Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no... (Review)
Review
INTRODUCTION
Experimental animal models constitute a useful tool to deepen our knowledge of central nervous system disorders. In the case of multiple sclerosis, however, there is no such specific model able to provide an overview of the disease; multiple models covering the different pathophysiological features of the disease are therefore necessary.
DEVELOPMENT
We reviewed the different in vitro and in vivo experimental models used in multiple sclerosis research. Concerning in vitro models, we analysed cell cultures and slice models. As for in vivo models, we examined such models of autoimmunity and inflammation as experimental allergic encephalitis in different animals and virus-induced demyelinating diseases. Furthermore, we analysed models of demyelination and remyelination, including chemical lesions caused by cuprizone, lysolecithin, and ethidium bromide; zebrafish; and transgenic models.
CONCLUSIONS
Experimental models provide a deeper understanding of the different pathogenic mechanisms involved in multiple sclerosis. Choosing one model or another depends on the specific aims of the study.
Topics: Animals; Cuprizone; Demyelinating Diseases; Humans; In Vitro Techniques; Multiple Sclerosis; Myelin Sheath; Remyelination
PubMed: 28863829
DOI: 10.1016/j.nrl.2017.07.002 -
Frontiers in Immunology 2020Microglia originate from myeloid progenitors in the embryonic yolk sac and play an integral role in central nervous system (CNS) development, immune surveillance and... (Review)
Review
Microglia originate from myeloid progenitors in the embryonic yolk sac and play an integral role in central nervous system (CNS) development, immune surveillance and repair. The role of microglia in multiple sclerosis (MS) has been complex and controversial, with evidence suggesting that these cells play key roles in both active inflammation and remyelination. Here we will review the most recent histological classification of MS lesions as well as the evidence supporting both inflammatory and reparative functions of these cells. We will also review how microglia may yield new biomarkers for MS activity and serve as a potential target for therapy.
Topics: Antirheumatic Agents; Biomarkers; Demyelinating Diseases; Genetic Diseases, Inborn; Humans; Immunologic Surveillance; Macrophages; Microglia; Multiple Sclerosis; Neurodegenerative Diseases; Neuroimaging; T-Lymphocyte Subsets
PubMed: 32265902
DOI: 10.3389/fimmu.2020.00374 -
Handbook of Clinical Neurology 2017Inflammatory demyelinating diseases are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. The... (Review)
Review
Inflammatory demyelinating diseases are a heterogeneous group of disorders, which occur against the background of an acute or chronic inflammatory process. The pathologic hallmark of multiple sclerosis (MS) is the presence of focal demyelinated lesions with partial axonal preservation and reactive astrogliosis. Demyelinated plaques are present in the white as well as gray matter, such as the cerebral or cerebellar cortex and brainstem nuclei. Activity of the disease process is reflected by the presence of lesions with ongoing myelin destruction. Axonal and neuronal destruction in the lesions is a major substrate for permanent neurologic deficit in MS patients. The MS pathology is qualitatively similar in different disease stages, such as relapsing remitting MS or secondary or primary progressive MS, but the prevalence of different lesion types differs quantitatively. Acute MS and Balo's type of concentric sclerosis appear to be variants of classic MS. In contrast, neuromyelitis optica (NMO) and spectrum disorders (NMOSD) are inflammatory diseases with primary injury of astrocytes, mediated by aquaporin-4 antibodies. Finally, we discuss the histopathology of other inflammatory demyelinating diseases such as acute disseminated encephalomyelitis and myelin oligodendrocyte glycoprotein antibody-associated demyelination. Knowledge of the heterogenous immunopathology in demyelinating diseases is important, to understand the clinical presentation and disease course and to find the optimal treatment for an individual patient.
Topics: Animals; Central Nervous System; Demyelinating Diseases; Humans
PubMed: 28987175
DOI: 10.1016/B978-0-12-802395-2.00019-5 -
Acta Neuropathologica Sep 2017Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age,... (Review)
Review
Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies.
Topics: Axons; Demyelinating Diseases; Humans; Myelin Sheath; Neuroglia; White Matter
PubMed: 28638987
DOI: 10.1007/s00401-017-1739-1 -
Glia Jul 2022In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The... (Review)
Review
In human demyelinating diseases such as multiple sclerosis (MS), an imbalance between demyelination and remyelination can trigger progressive degenerative processes. The clearance of myelin debris (phagocytosis) from the site of demyelination by microglia is critically important to achieve adequate remyelination and to slow the progression of the disease. However, how microglia phagocytose the myelin debris, and why clearance is impaired in MS, is not fully known; likewise, the role of the microglia in remyelination remains unclear. Recent studies using cuprizone (CPZ) as an animal model of central nervous system demyelination revealed that the up-regulation of signaling proteins in microglia facilitates effective phagocytosis of myelin debris. Moreover, during demyelination, protective mediators are released from activated microglia, resulting in the acceleration of remyelination in the CPZ model. In contrast, inadequate microglial activation or recruitment to the site of demyelination, and the production of toxic mediators, impairs remyelination resulting in progressive demyelination. In addition to the microglia-mediated phagocytosis, astrocytes play an important role in the phagocytic process by recruiting microglia to the site of demyelination and producing regenerative mediators. The current review is an update of these emerging findings from the CPZ animal model, discussing the roles of microglia and astrocytes in phagocytosis and myelination.
Topics: Animals; Astrocytes; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin Sheath; Phagocytosis
PubMed: 35107839
DOI: 10.1002/glia.24148 -
Neuroscience Bulletin Apr 2013
Topics: Animals; Brain; Demyelinating Diseases; Humans; Myelin Sheath
PubMed: 23558586
DOI: 10.1007/s12264-013-1325-z -
Anaesthesia Sep 1980The demyelinating diseases are classified and the current concepts of the aetiology and pathophysiology of the most common of these diseases, multiple sclerosis, are... (Review)
Review
The demyelinating diseases are classified and the current concepts of the aetiology and pathophysiology of the most common of these diseases, multiple sclerosis, are described. The effects of the impaired function, local responses and known complications of the disease on the choice of anaesthetic, drugs and techniques are discussed.
Topics: Anesthesia, General; Anesthesia, Local; Demyelinating Diseases; Humans; Multiple Sclerosis; Preoperative Care
PubMed: 7004260
DOI: 10.1111/j.1365-2044.1980.tb03947.x -
Cells Mar 2020Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of... (Review)
Review
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Various pre-clinical models with different specific features of the disease are available to study MS pathogenesis and to develop new therapeutic options. During the last decade, the model of toxic demyelination induced by cuprizone has become more and more popular, and it has contributed substantially to our understanding of distinct yet important aspects of the MS pathology. Here, we aim to provide a practical guide on how to use the cuprizone model and which pitfalls should be avoided.
Topics: Animals; Body Weight; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Multiple Sclerosis
PubMed: 32244377
DOI: 10.3390/cells9040843 -
Journal of Neuroscience Research Nov 2009The capacity to fold proteins properly is fundamental for cell survival. Secreted and transmembrane proteins are synthesized in the endoplasmic reticulum (ER), an... (Review)
Review
The capacity to fold proteins properly is fundamental for cell survival. Secreted and transmembrane proteins are synthesized in the endoplasmic reticulum (ER), an organelle that has the ability to discriminate between native and nonnative proteins, in a process called protein quality control. When folding is not properly achieved, misfolded proteins can accumulate. The terminally misfolded proteins are typically retrotranslocated into the cytoplasm for degradation by the proteasome, in a process known as endoplasmic reticulum-associated degradation. However, if the degradation is insufficient, accumulation of abnormal proteins in the ER activates the unfolded protein response (UPR), a complex set of new signals aimed to reduce further the load of abnormal protein in the ER. Massive synthesis of myelin lipids and proteins is necessary to support myelinogenesis. Not surprisingly, therefore, ER stress (including the UPR), the proteasome, and autophagy (lysosomes) have been implicated in myelin disorders, such as Pelizaeus-Merzbacher disease and vanishing white matter disease in the central nervous system and Charcot-Marie-Tooth neuropathies in the peripheral nervous system. Here we discuss recent evidence supporting an important role for ER stress in myelin disorders.
Topics: Animals; Autophagy; Demyelinating Diseases; Disease Models, Animal; Endoplasmic Reticulum; Humans; Lysosomes; Myelin Proteins; Proteasome Endopeptidase Complex; Protein Folding; Stress, Physiological; Unfolded Protein Response
PubMed: 19330777
DOI: 10.1002/jnr.22066