-
Nature Communications Oct 2023Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia...
Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8 T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.
Topics: Animals; Mice; Axons; CD8-Positive T-Lymphocytes; Demyelinating Diseases; Microglia; Myelin Sheath; Neuroinflammatory Diseases
PubMed: 37903797
DOI: 10.1038/s41467-023-42570-2 -
Nature Communications Dec 2023Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD),...
Heterozygous deletions in the ANKS1B gene cause ANKS1B neurodevelopmental syndrome (ANDS), a rare genetic disease characterized by autism spectrum disorder (ASD), attention deficit/hyperactivity disorder, and speech and motor deficits. The ANKS1B gene encodes for AIDA-1, a protein that is enriched at neuronal synapses and regulates synaptic plasticity. Here we report an unexpected role for oligodendroglial deficits in ANDS pathophysiology. We show that Anks1b-deficient mouse models display deficits in oligodendrocyte maturation, myelination, and Rac1 function, and recapitulate white matter abnormalities observed in ANDS patients. Selective loss of Anks1b from the oligodendrocyte lineage, but not from neuronal populations, leads to deficits in social preference and sensory reactivity previously observed in a brain-wide Anks1b haploinsufficiency model. Furthermore, we find that clemastine, an antihistamine shown to increase oligodendrocyte precursor cell maturation and central nervous system myelination, rescues deficits in social preference in 7-month-old Anks1b-deficient mice. Our work shows that deficits in social behaviors present in ANDS may originate from abnormal Rac1 activity within oligodendrocytes.
Topics: Animals; Humans; Infant; Mice; Autism Spectrum Disorder; Intracellular Signaling Peptides and Proteins; Neurons; Oligodendroglia; Social Behavior
PubMed: 38129387
DOI: 10.1038/s41467-023-43438-1 -
Translational Neurodegeneration Nov 2023Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity... (Review)
Review
Oligodendrocyte progenitor cells (OPCs) play pivotal roles in myelin formation and phagocytosis, communicating with neighboring cells and contributing to the integrity of the blood-brain barrier (BBB). However, under the pathological circumstances of Alzheimer's disease (AD), the brain's microenvironment undergoes detrimental changes that significantly impact OPCs and their functions. Starting with OPC functions, we delve into the transformation of OPCs to myelin-producing oligodendrocytes, the intricate signaling interactions with other cells in the central nervous system (CNS), and the fascinating process of phagocytosis, which influences the function of OPCs and affects CNS homeostasis. Moreover, we discuss the essential role of OPCs in BBB formation and highlight the critical contribution of OPCs in forming CNS-protective barriers. In the context of AD, the deterioration of the local microenvironment in the brain is discussed, mainly focusing on neuroinflammation, oxidative stress, and the accumulation of toxic proteins. The detrimental changes disturb the delicate balance in the brain, impacting the regenerative capacity of OPCs and compromising myelin integrity. Under pathological conditions, OPCs experience significant alterations in migration and proliferation, leading to impaired differentiation and a reduced ability to produce mature oligodendrocytes. Moreover, myelin degeneration and formation become increasingly active in AD, contributing to progressive neurodegeneration. Finally, we summarize the current therapeutic approaches targeting OPCs in AD. Strategies to revitalize OPC senescence, modulate signaling pathways to enhance OPC differentiation, and explore other potential therapeutic avenues are promising in alleviating the impact of AD on OPCs and CNS function. In conclusion, this review highlights the indispensable role of OPCs in CNS function and their involvement in the pathogenesis of AD. The intricate interplay between OPCs and the AD brain microenvironment underscores the complexity of neurodegenerative diseases. Insights from studying OPCs under pathological conditions provide a foundation for innovative therapeutic strategies targeting OPCs and fostering neurodegeneration. Future research will advance our understanding and management of neurodegenerative diseases, ultimately offering hope for effective treatments and improved quality of life for those affected by AD and related disorders.
Topics: Humans; Alzheimer Disease; Oligodendrocyte Precursor Cells; Quality of Life; Oligodendroglia; Cell Differentiation
PubMed: 37964328
DOI: 10.1186/s40035-023-00385-7 -
Trends in Molecular Medicine Oct 2023Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of... (Review)
Review
Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter (WM) structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT (mHTT). We also discuss potential therapeutic implications involving these molecular pathways.
Topics: Humans; Huntington Disease; Oligodendroglia; Myelin Sheath; Neuroglia; Axons
PubMed: 37591764
DOI: 10.1016/j.molmed.2023.07.010 -
Molecular Brain Sep 2023Parkinson's disease (PD) is characterized by a selective loss of dopaminergic neurons. While most research on PD conducted to date has focused on neurons and, to a...
Parkinson's disease (PD) is characterized by a selective loss of dopaminergic neurons. While most research on PD conducted to date has focused on neurons and, to a certain extent, glia, few studies have investigated changes in oligodendroglia. Here, we investigated the heterogeneity of oligodendrocytes from PD patients compared with those of control cases by analyzing single-nuclei transcriptomes. These analyses revealed the presence of distinct oligodendrocyte populations in PD patients indicative of corresponding variations in molecular features, notably including activation of inflammatory responses, response to protein folding stress, and myelination abnormalities. We confirmed myelination abnormalities in an α-synuclein preformed fibril-injection mouse model of PD. These results suggest that oligodendrocytes acquire disease-associated phenotypes in PD and may contribute to the accompanying neurodegeneration.
Topics: Animals; Mice; Parkinson Disease; Oligodendroglia; Neuroglia; Cytoskeleton; Dopaminergic Neurons
PubMed: 37710343
DOI: 10.1186/s13041-023-01055-5 -
Current Opinion in Neurobiology Dec 2023Oligodendrocytes are best known for wrapping myelin, a unique specialization that enables energy-efficient and fast axonal impulse propagation in white matter tracts and... (Review)
Review
Oligodendrocytes are best known for wrapping myelin, a unique specialization that enables energy-efficient and fast axonal impulse propagation in white matter tracts and fibers of the cortical circuitry. However, myelinating oligodendrocytes have additional metabolic functions that are only gradually understood, including the regulated release of pyruvate/lactate and extracellular vesicles, both of which are in support of the axonal energy balance. The axon-supportive functions of glial cells are older than myelin in nervous system evolution and implicate oligodendrocyte dysfunction and loss of myelin integrity as a risk factor for progressive neurodegeneration in brain diseases.
Topics: Myelin Sheath; Oligodendroglia; Brain; Axons; Energy Metabolism
PubMed: 37703600
DOI: 10.1016/j.conb.2023.102782 -
Molecular Neurobiology Sep 2023Ischemic stroke is one of the main reasons of disability and death. Stroke-induced functional deficits are mainly due to the secondary degeneration of the white matter... (Review)
Review
Ischemic stroke is one of the main reasons of disability and death. Stroke-induced functional deficits are mainly due to the secondary degeneration of the white matter characterized by axonal demyelination and injury of axon-glial integrity. Enhancement of the axonal regeneration and remyelination could promote the neural functional recovery. However, cerebral ischemia-induced activation of RhoA/Rho kinase (ROCK) pathway plays a crucial and harmful role in the process of axonal recovery and regeneration. Inhibition of this pathway could promote the axonal regeneration and remyelination. In addition, hydrogen sulfide (HS) has the significant neuroprotective role during the recovery of ischemic stroke via inhibiting the inflammatory response and oxidative stress, regulating astrocyte function, promoting the differentiation of endogenous oligodendrocyte precursor cells (OPCs) to mature oligodendrocyte. Among all of these effects, promoting the formation of mature oligodendrocyte is a crucial part of axonal regeneration and remyelination. Furthermore, numerous studies have uncovered the crosstalk between astrocytes and oligodendrocyte, microglial cells and oligodendrocyte in the axonal remyelination following ischemic stroke. The purpose of this review was to discuss the relationship among HS, RhoA/ROCK pathway, astrocytes, and microglial cells in the axonal remyelination following ischemic stroke to reveal new strategies for preventing and treating this devastating disease.
Topics: Humans; Remyelination; Ischemic Stroke; rho-Associated Kinases; Neuroglia; Oligodendroglia; Axons; Stroke; Cell Differentiation
PubMed: 37322287
DOI: 10.1007/s12035-023-03422-8 -
Cold Spring Harbor Perspectives in... May 2024This is a review of inherited and acquired causes of human demyelinating neuropathies and a subset of disorders that affect axon-Schwann cell interactions. Nearly all... (Review)
Review
This is a review of inherited and acquired causes of human demyelinating neuropathies and a subset of disorders that affect axon-Schwann cell interactions. Nearly all inherited demyelinating neuropathies are caused by mutations in genes that are expressed by myelinating Schwann cells, affecting diverse functions in a cell-autonomous manner. The most common acquired demyelinating neuropathies are Guillain-Barré syndrome and chronic, inflammatory demyelinating polyneuropathy, both of which are immune-mediated. An additional group of inherited and acquired disorders affect axon-Schwann cell interactions in the nodal region. Overall, these disorders affect the formation of myelin and its maintenance, with superimposed axonal loss that is clinically important.
Topics: Humans; Myelin Sheath; Schwann Cells; Demyelinating Diseases; Animals; Peripheral Nervous System; Axons; Peripheral Nervous System Diseases; Guillain-Barre Syndrome
PubMed: 38253417
DOI: 10.1101/cshperspect.a041376 -
Current Opinion in Neurobiology Jun 2024Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important... (Review)
Review
Microglia are tissue-resident macrophages and professional phagocytes of the central nervous system (CNS). In development, microglia-mediated phagocytosis is important for sculpting the cellular architecture. This includes the engulfment of dead/dying cells, pruning extranumerary synapses and axons, and phagocytosing fragments of myelin sheaths. Intriguingly, these developmental phagocytic mechanisms by which microglia sculpt the CNS are now appreciated as important for eliminating synapses, myelin, and proteins during neurodegeneration. Here, we discuss parallels between neurodevelopment and neurodegeneration, which highlights how development is informing disease. We further discuss recent advances and challenges towards therapeutically targeting these phagocytic pathways and how we can leverage development to overcome these challenges.
Topics: Humans; Microglia; Animals; Phagocytosis; Neurodegenerative Diseases; Myelin Sheath; Central Nervous System
PubMed: 38631077
DOI: 10.1016/j.conb.2024.102877 -
The Journal of Endocrinology Aug 2023Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells (SCs) in the peripheral nervous system. Glucocorticoid hormones are major...
Myelination allows fast and synchronized nerve influxes and is provided by Schwann cells (SCs) in the peripheral nervous system. Glucocorticoid hormones are major regulators of stress, metabolism and immunity affecting all tissues. They act by binding to two receptors, the low-affinity glucocorticoid receptor (GR) and the high-affinity mineralocorticoid receptor (MR). Little is known about the effect of glucocorticoid hormones on the PNS, and this study focuses on deciphering the role of MR in peripheral myelination. In this work, the presence of a functional MR in SCs is demonstrated and the expression of MR protein in mouse sciatic nerve SC is evidenced. Besides, knockout of MR in SC (SCMRKO using Cre-lox system with DesertHedgeHog (Dhh) Cre promoter) was undertaken in mice. SCMRKO was not associated with alterations of performance in motor behavioral tests on 2- to 6-month-old male mice compared to their controls. No obvious modifications of myelin gene expression or MR signaling gene expression were observed in the SCMRKO sciatic nerves. Nevertheless, Gr transcript and GR protein amounts were significantly increased in SCMRKO nerves compared to controls, suggesting a possible compensatory effect. Besides, an increase in myelin sheath thickness was noted for axons with perimeters larger than 15 µm in SCMRKO illustrated by a significant 4.5% reduction in g-ratio (axon perimeter/myelin sheath perimeter). Thus, we defined MR as a new player in peripheral system myelination and in SC homeostasis.
Topics: Male; Mice; Animals; Myelin Sheath; Receptors, Mineralocorticoid; Glucocorticoids; Mice, Knockout; Schwann Cells; Sciatic Nerve
PubMed: 37195271
DOI: 10.1530/JOE-22-0334