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Cell Reports Dec 2023Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for...
Multiple sclerosis (MS) is an inflammatory disease characterized by myelin loss. While therapies exist to slow MS progression, no treatment currently exists for remyelination. Remyelination, linked to reduced disability in MS, relies on microglia and monocyte-derived macrophages (MDMs). This study aims to understand the role of microglia during remyelination by lineage tracing and depleting them. Microglial lineage tracing reveals that both microglia and MDMs initially accumulate, but microglia later dominate the lesion. Microglia and MDMs engulf equal amounts of inhibitory myelin debris, but after microglial depletion, MDMs compensate by engulfing more myelin debris. Microglial depletion does, however, reduce the recruitment and proliferation of oligodendrocyte progenitor cells (OPCs) and impairs their subsequent differentiation and remyelination. These findings underscore the essential role of microglia during remyelination and offer insights for enhancing this process by understanding microglial regulation of remyelination.
Topics: Humans; Myelin Sheath; Microglia; Remyelination; Demyelinating Diseases; Macrophages; Multiple Sclerosis
PubMed: 38100356
DOI: 10.1016/j.celrep.2023.113574 -
Progress in Neurobiology Jul 2023Oligodendrocytes are responsible for myelinating central nervous system (CNS) axons and rapid electrical transmission through saltatory conduction of action potentials.... (Review)
Review
Oligodendrocytes are responsible for myelinating central nervous system (CNS) axons and rapid electrical transmission through saltatory conduction of action potentials. Myelination and myelin repair rely partially on oligodendrogenesis, which comprises oligodendrocyte precursor cell (OPC) migration, maturation, and differentiation into oligodendrocytes (OL). In multiple sclerosis (MS), demyelination occurs due to an inflammatory cascade with auto-reactive T-cells. When oligodendrogenesis fails, remyelination becomes aberrant and conduction impairments are no longer restored. Although current disease modifying therapies have achieved results in modulating the faulty immune response, disease progression continues because of chronic inflammation, neurodegeneration, and failure of remyelination. Therapies have been tried to promote remyelination. Modulation of neuronal activity seems to be a very promising strategy in preclinical studies. Additionally, studies in people with MS (pwMS) have shown symptom improvement following non-invasive brain stimulation. (NIBS) techniques. The aforementioned mechanisms are yet unknown and probably involve both the activation of neurons and glial cells. Noting neuronal activity contributes to myelin plasticity and that NIBS modulates neuronal activity; we argue that NIBS is a promising research horizon for demyelinating diseases. We review the hypothesized pathways through which NIBS may affect both neuronal activity in the CNS and how the resulting activity can affect oligodendrogenesis and myelination.
Topics: Humans; Remyelination; Myelin Sheath; Oligodendroglia; Multiple Sclerosis; Cell Differentiation
PubMed: 37127087
DOI: 10.1016/j.pneurobio.2023.102459 -
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 -
Neural Regeneration Research Jul 2023Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral... (Review)
Review
Charcot-Marie-Tooth neuropathies (CMT) constitute a group of common but highly heterogeneous, non-syndromic genetic disorders affecting predominantly the peripheral nervous system. CMT type 1A (CMT1A) is the most frequent type and accounts for almost ~50% of all diagnosed CMT cases. CMT1A results from the duplication of the peripheral myelin protein 22 (PMP22) gene. Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response. This leads to Schwann cell apoptosis, dys- and de- myelination and secondary axonal degeneration, ultimately causing neurological disabilities. During the last decades, several different gene therapies have been developed to treat CMT1A. Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22. The therapeutic goal is to achieve gene silencing, directly or indirectly, thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss. As promising treatments are rapidly emerging, treatment-responsive and clinically relevant biomarkers are becoming necessary. These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A.
PubMed: 36571339
DOI: 10.4103/1673-5374.361538 -
Brain : a Journal of Neurology Aug 2023Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process...
Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.
Topics: Humans; Animals; Mice; Clemastine; Autism Spectrum Disorder; Pharmaceutical Preparations; Intellectual Disability
PubMed: 37068912
DOI: 10.1093/brain/awad057 -
Current Opinion in Cell Biology Feb 2024Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to... (Review)
Review
Multiple Sclerosis (MS) is a common cause of impairment in working-aged adults. MS is characterized by neuroinflammation and infiltration of peripheral immune cells to the brain, which cause myelin loss and death of oligodendrocytes and neurons. Many studies on MS have focused on the peripheral immune sources of demyelination and repair. However, recent studies revealed that a glial cell type, the astrocytes, undergo robust morphological and transcriptomic changes that contribute significantly to demyelination and myelin repair. Here, we discuss recent findings elucidating signaling modalities that astrocytes acquire or lose in MS and how these changes alter the interactions of astrocytes with other nervous system cell types.
Topics: Humans; Multiple Sclerosis; Astrocytes; Myelin Sheath; Oligodendroglia; Neurons
PubMed: 38145604
DOI: 10.1016/j.ceb.2023.102307 -
Comprehensive Psychoneuroendocrinology Nov 2023Although there is a consistent literature documenting that vagal cardioinhibitory pathways support homeostatic functions, another less frequently cited literature... (Review)
Review
Although there is a consistent literature documenting that vagal cardioinhibitory pathways support homeostatic functions, another less frequently cited literature implicates vagal cardioinhibitory pathways in compromises to survival in humans and other mammals. The latter is usually associated with threat reactions, chronic stress, and potentially lethal clinical conditions such as hypoxia. Solving this 'vagal paradox' in studies conducted in the neonatal intensive care unit served as the motivator for the Polyvagal Theory (PVT). The paradox is resolved when the different functions of vagal cardioinhibitory fibers originating in two anatomically distinguishable brainstem areas are recognized. One pathway originates in a dorsal area known as the dorsal motor nucleus of the vagus and the other in a ventral area of the brainstem known as nucleus ambiguus. Unlike mammals, in all ancestral vertebrates from which mammals evolved, cardioinhibitory vagal fibers primarily originate in the dorsal motor nucleus of the vagus. Thus, in mammals the vagus nerve is 'poly' vagal because it contains two distinct efferent pathways. Developmental and evolutionary biology identify a ventral migration of vagal cardioinhibitory fibers that culminate in an integrated circuit that has been labeled the ventral vagal complex. This complex consists of the interneuronal communication of the ventral vagus with the source nuclei involved in regulating the striated muscles of the head and face via special visceral efferent pathways. This integrated system enables the coordination of vagal regulation of the heart with sucking, swallowing, breathing, and vocalizing and forms the basis of a social engagement system that allows sociality to be a potent neuromodulator resulting in calm states that promote homeostatic function. These biobehavioral features, dependent on the maturation of the ventral vagal complex, can be compromised in preterm infants. Developmental biology informs us that in the immature mammal (e.g., fetus, preterm infant) the ventral vagus is not fully functional and myelinization is not complete; this neuroanatomical profile may potentiate the impact of vagal cardioinhibitory pathways originating in the dorsal motor nucleus of the vagus. This vulnerability is confirmed clinically in the life-threatening reactions of apnea and bradycardia in human preterm newborns, which are hypothetically mediated through chronotropic dorsal vagal pathways. Neuroanatomical research documents that the distribution of cardioinhibitory neurons representing these two distinct vagal source nuclei varies among mammals and changes during early development. By explaining the solution of the 'vagal paradox' in the preterm human, the paper highlights the functional cardioinhibitory functions of the two vagal source nuclei and provides the scientific foundation for the testing of hypotheses generated by PVT.
PubMed: 38108034
DOI: 10.1016/j.cpnec.2023.100200 -
IScience Oct 2023Multiple sclerosis (MS) is a leading disease that causes disability in young adults. We have previously shown that a DEAD-box RNA helicase Ddx54 binds to mRNA and...
Multiple sclerosis (MS) is a leading disease that causes disability in young adults. We have previously shown that a DEAD-box RNA helicase Ddx54 binds to mRNA and protein isoforms of myelin basic protein (MBP) and that Ddx54 siRNA blocking abrogates oligodendrocyte migration and myelination. Herein, we show that MBP-driven Ddx54 knockout mice (), after the completion of normal postnatal myelination, gradually develop abnormalities in behavioral profiles and learning ability, inner myelin sheath breakdown, loss of myelinated axons, apoptosis of oligodendrocytes, astrocyte and microglia activation, and they die within 7 months but show minimal peripheral immune cell infiltration. Myelin in is highly vulnerable to the neurotoxicant cuprizone and Ddx54 knockdown greatly impairs myelination . Ddx54 expression in oligodendrocyte-lineage cells decreased in corpus callosum of MS patients. Our results demonstrate that Ddx54 is indispensable for myelin homeostasis, and they provide a demyelinating disease model based on intrinsic disintegration of adult myelin.
PubMed: 37720086
DOI: 10.1016/j.isci.2023.107448