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Neurologia Oct 2018Alexander disease (AxD) is a type of leukodystrophy. Its pathological basis, along with myelin loss, is the appearance of Rosenthal bodies, which are cytoplasmic... (Review)
Review
INTRODUCTION
Alexander disease (AxD) is a type of leukodystrophy. Its pathological basis, along with myelin loss, is the appearance of Rosenthal bodies, which are cytoplasmic inclusions in astrocytes. Mutations in the gene coding for GFAP have been identified as a genetic basis for AxD. However, the mechanism by which these variants produce the disease is not understood.
DEVELOPMENT
The most widespread hypothesis is that AxD develops when a gain of function mutation causes an increase in GFAP. However, this mechanism does not explain myelin loss, given that experimental models in which GFAP expression is normal or mutated do not exhibit myelin disorders. This review analyses other possibilities that may explain this alteration, such as epigenetic or inflammatory alterations, presence of NG2 (+) - GFAP (+) cells, or post-translational modifications in GFAP that are unrelated to increased expression.
CONCLUSIONS
The different hypotheses analysed here may explain the myelin alteration affecting these patients, and multiple mechanisms may coexist. These theories raise the possibility of designing therapies based on these mechanisms.
Topics: Alexander Disease; Animals; Glial Fibrillary Acidic Protein; Humans; Myelin Sheath
PubMed: 28342553
DOI: 10.1016/j.nrl.2017.01.019 -
Aging and Disease Apr 2024Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and cognitive decline. Despite significant efforts over several... (Review)
Review
Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and cognitive decline. Despite significant efforts over several decades, our understanding of the pathophysiology of this disease is still incomplete. Myelin is a multi-layered membrane structure ensheathing neuronal axons, which is essential for the fast and effective propagation of action potentials along the axons. Recent studies highlight the critical involvement of myelin in memory consolidation and reveal its vulnerability in various pathological conditions. Notably, apart from the classic amyloid hypothesis, myelin degeneration has been proposed as another critical pathophysiological feature of AD, which could occur prior to the development of amyloid pathology. Here, we review recent works supporting the critical role of myelin in cognition and myelin pathology during AD progression, with a focus on the mechanisms underlying myelin degeneration in AD. We also discuss the complex intersections between myelin pathology and typical AD pathophysiology, as well as the therapeutic potential of pro-myelinating approaches for this disease. Overall, these findings implicate myelin degeneration as a critical contributor to AD-related cognitive deficits and support targeting myelin repair as a promising therapeutic strategy for AD.
Topics: Humans; Alzheimer Disease; Myelin Sheath; Neurodegenerative Diseases; Axons; Cognition Disorders
PubMed: 37548935
DOI: 10.14336/AD.2023.0628 -
Neuropharmacology Nov 2016Impact to the head or rapid head acceleration-deceleration can cause traumatic brain injury (TBI) with a characteristic pathology of traumatic axonal injury (TAI) and... (Review)
Review
Impact to the head or rapid head acceleration-deceleration can cause traumatic brain injury (TBI) with a characteristic pathology of traumatic axonal injury (TAI) and secondary damage in white matter tracts. Myelin and oligodendrocyte lineage cells have significant roles in the progression of white matter pathology after TBI and in the potential for plasticity and subsequent recovery. The myelination pattern of specific brain regions, such as frontal cortex, may also increase susceptibility to neurodegeneration and psychiatric symptoms after TBI. White matter pathology after TBI depends on the extent and distribution of axon damage, microhemorrhages and/or neuroinflammation. TAI occurs in a pattern of damaged axons dispersed among intact axons in white matter tracts. TAI accompanied by bleeding and/or inflammation produces focal regions of overt tissue destruction, resulting in loss of both axons and myelin. White matter regions with TAI may also exhibit demyelination of intact axons. Demyelinated axons that remain viable have the potential for remyelination and recovery of function. Indeed, animal models of TBI have demonstrated demyelination that is associated with evidence of remyelination, including oligodendrocyte progenitor cell proliferation, generation of new oligodendrocytes, and formation of thinner myelin. Changes in neuronal activity that accompany TBI may also involve myelin remodeling, which modifies conduction efficiency along intact myelinated fibers. Thus, effective remyelination and myelin remodeling may be neurobiological substrates of plasticity in neuronal circuits that require long-distance communication. This perspective integrates findings from multiple contexts to propose a model of myelin and oligodendrocyte lineage cell relevance in white matter injury after TBI. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
Topics: Animals; Brain Injuries, Traumatic; Cell Plasticity; Humans; Myelin Sheath; Oligodendroglia; White Matter
PubMed: 25963414
DOI: 10.1016/j.neuropharm.2015.04.029 -
International Journal of Molecular... Aug 2021Niemann-Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by... (Review)
Review
Niemann-Pick type C (NPC) disease is a wide-spectrum clinical condition classified as a neurovisceral disorder affecting mainly the liver and the brain. It is caused by mutations in one of two genes, and , coding for proteins located in the lysosomes. NPC proteins are deputed to transport cholesterol within lysosomes or between late endosome/lysosome systems and other cellular compartments, such as the endoplasmic reticulum and plasma membrane. The first trait of NPC is the accumulation of unesterified cholesterol and other lipids, like sphingosine and glycosphingolipids, in the late endosomal and lysosomal compartments, which causes the blockade of autophagic flux and the impairment of mitochondrial functions. In the brain, the main consequences of NPC are cerebellar neurodegeneration, neuroinflammation, and myelin defects. This review will focus on myelin defects and the pivotal importance of cholesterol for myelination and will offer an overview of the molecular targets and the pharmacological strategies so far proposed, or an object of clinical trials for NPC. Finally, it will summarize recent data on a new and promising pharmacological perspective involving A adenosine receptor stimulation in genetic and pharmacological NPC dysmyelination models.
Topics: Adenosine A2 Receptor Agonists; Animals; Cholesterol; Humans; Myelin Sheath; Niemann-Pick Disease, Type C; Receptor, Adenosine A2A
PubMed: 34445564
DOI: 10.3390/ijms22168858 -
Aging May 2018
Topics: Animals; Humans; Lipids; Myelin Sheath
PubMed: 29788000
DOI: 10.18632/aging.101458 -
The Journal of Physiological Sciences :... Mar 2016Rapid action potential propagation along myelinated axons requires voltage-gated Na(+) channel clustering at the axon initial segments (AISs) and nodes of Ranvier. The... (Review)
Review
Rapid action potential propagation along myelinated axons requires voltage-gated Na(+) channel clustering at the axon initial segments (AISs) and nodes of Ranvier. The AIS is intrinsically defined by cytoskeletal proteins expressed in axons, whereas nodes of Ranvier are formed by interaction between neurons and myelinating glia. These axonal domains have long been considered stable structures, but recent studies revealed that they are plastic and contribute to fine adjustment of neuronal activities and circuit function. The AIS changes its distribution and maintains neural circuit activity at a constant level. Morphological changes in myelinated nerve structures presumably modulate the excitability of nodal regions and regulate the timing of activity, thereby optimizing signal processing in a neural circuit. This review highlights recent findings on the structural plasticity of these excitable axonal domains.
Topics: Action Potentials; Animals; Axons; Myelin Sheath; Neuroglia; Neuronal Plasticity
PubMed: 26464228
DOI: 10.1007/s12576-015-0413-4 -
Trends in Cell Biology Feb 2016The evolutionary success of the vertebrate nervous system is largely due to a unique structural feature--the myelin sheath, a fatty envelope that surrounds the axons of... (Review)
Review
The evolutionary success of the vertebrate nervous system is largely due to a unique structural feature--the myelin sheath, a fatty envelope that surrounds the axons of neurons. By increasing the speed by which electrical signals travel along axons, myelin facilitates neuronal communication between distant regions of the nervous system. We review the cellular and molecular mechanisms that regulate the development of myelin as well as its homeostasis in adulthood. We discuss how finely tuned neuron-oligodendrocyte interactions are central to myelin formation during development and in the adult, and how these interactions can have profound implications for the plasticity of the adult brain. We also speculate how the functional diversity of both neurons and oligodendrocytes may impact on the myelination process in both health and disease.
Topics: Adult; Animals; Axons; Biological Evolution; Humans; Myelin Sheath; Neurons; Oligodendroglia; Synaptic Transmission
PubMed: 26442841
DOI: 10.1016/j.tcb.2015.09.002 -
Glia Dec 2022Peripheral nerves and Schwann cells have to sustain constant mechanical constraints, caused by developmental growth as well as stretches associated with movements of the...
Peripheral nerves and Schwann cells have to sustain constant mechanical constraints, caused by developmental growth as well as stretches associated with movements of the limbs and mechanical compressions from daily activities. In Schwann cells, signaling molecules sensitive to stiffness or stretch of the extracellular matrix, such as YAP/TAZ, have been shown to be critical for Schwann cell development and peripheral nerve regeneration. YAP/TAZ have also been suggested to contribute to tumorigenesis, neuropathic pain, and inherited disorders. Yet, the role of mechanosensitive ion channels in myelinating Schwann cells is vastly unexplored. Here we comprehensively assessed the expression of mechanosensitive ion channels in Schwann cells and identified that PIEZO1 and PIEZO2 are among the most abundant mechanosensitive ion channels expressed by Schwann cells. Using classic genetic ablation studies, we show that PIEZO1 is a transient inhibitor of radial and longitudinal myelination in Schwann cells. Contrastingly, we show that PIEZO2 may be required for myelin formation, as the absence of PIEZO2 in Schwann cells delays myelin formation. We found an epistatic relationship between PIEZO1 and PIEZO2, at both the morphological and molecular levels. Finally, we show that PIEZO1 channels affect the regulation of YAP/TAZ activation in Schwann cells. Overall, we present here the first demonstration that PIEZO1 and PIEZO2 contribute to mechanosensation in Schwann cells as well myelin development in the peripheral nervous system.
Topics: Ion Channels; Myelin Sheath; Neurogenesis; Schwann Cells
PubMed: 35903933
DOI: 10.1002/glia.24251 -
Neuroscience Sep 2014Myelination by oligodendrocytes is a highly specialized process that relies on intimate interactions between the axon and the oligodendrocytes. Astrocytes have an... (Review)
Review
Myelination by oligodendrocytes is a highly specialized process that relies on intimate interactions between the axon and the oligodendrocytes. Astrocytes have an important part in facilitating myelination in the CNS, however, comparatively less is known about how they affect myelination. This review therefore summarizes the literature and explores lingering questions surrounding differences between white matter and gray matter astrocytes, how astrocytes support myelination, how their dysfunction in pathological states contributes to myelin pathologies and how astrocytes may facilitate remyelination. We discuss how astrocytes in the white matter are specialized to promote myelination and myelin maintenance by clearance of extracellular ions and neurotransmitters and by secretion of pro-myelinating factors. Additionally, astrocyte-oligodendrocyte coupling via gap junctions is crucial for both myelin formation and maintenance, due to K(+) buffering and possibly metabolic support for oligodendrocytes via the panglial syncytium. Dysfunctional astrocytes aberrantly affect oligodendrocytes, as exemplified by a number of leukodystrophies in which astrocytic pathology is known as the direct cause of myelin pathology. Conversely, in primary demyelinating diseases, such as multiple sclerosis, astrocytes may facilitate remyelination. We suggest that specific manipulation of astrocytes could help prevent myelin pathologies and successfully restore myelin sheaths after demyelination.
Topics: Animals; Astrocytes; Gray Matter; Humans; Multiple Sclerosis; Myelin Sheath; Oligodendroglia; White Matter
PubMed: 24231735
DOI: 10.1016/j.neuroscience.2013.10.050 -
Journal of Neurochemistry Feb 2019Myelin, the multilayered membrane surrounding many axons in the nervous system, increases the speed by which electrical signals travel along axons and facilitates... (Review)
Review
Myelin, the multilayered membrane surrounding many axons in the nervous system, increases the speed by which electrical signals travel along axons and facilitates neuronal communication between distant regions of the nervous system. However, how neuronal signals influence the myelinating process in the CNS is still largely unclear. Recent studies have significantly advanced this understanding, identifying important roles for neuronal activity in controlling oligodendrocyte development and their capacity of producing myelin in both developing and mature CNS. Here, we review these recent advances, and discuss potential mechanisms underpinning activity-dependent myelination and how remyelination may be stimulated via manipulating axonal activity, raising new questions for future research.
Topics: Animals; Cell Differentiation; Central Nervous System; Humans; Myelin Sheath; Neurogenesis; Oligodendroglia
PubMed: 30225984
DOI: 10.1111/jnc.14592