Lysosomal TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism.

TMEM106B is an endolysosomal transmembrane protein not only associated with multiple neurological disorders including frontotemporal dementia, Alzheimer's disease, and hypomyelinating leukodystrophy but also potentially involved in COVID-19. Additionally, recent studies have identified amyloid fibrils of C-terminal TMEM106B in both aged healthy and neurodegenerative brains. However, so far little is known about physiological functions of TMEM106B in the endolysosome and how TMEM106B is involved in a wide range of human conditions at molecular levels. Here, we performed lipidomic analysis of the brain of TMEM106B-deficient mice. We found that TMEM106B deficiency significantly decreases levels of two major classes of myelin lipids, galactosylceramide and its sulfated derivative sulfatide. Subsequent co-immunoprecipitation assay showed that TMEM106B physically interacts with galactosylceramidase. We also found that galactosylceramidase activity was significantly increased in TMEM106B-deficient brains. Thus, our results suggest that TMEM106B interacts with galactosylceramidase to regulate myelin lipid metabolism and have implications for TMEM106B-associated diseases.

Trem2-deficiency aggravates and accelerates age-related myelin degeneration.

Aging is the greatest known risk factor for most neurodegenerative diseases. Myelin degeneration is an early pathological indicator of these diseases and a normal part of aging; albeit, to a lesser extent. Despite this, little is known about the contribution of age-related myelin degeneration on neurodegenerative disease. Microglia participate in modulating white matter events from demyelination to remyelination, including regulation of (de)myelination by the microglial innate immune receptor triggering receptor expressed on myeloid cells 2 (TREM2). Here, we demonstrate Trem2-deficiency aggravates and accelerates age-related myelin degeneration in the striatum. We show TREM2 is necessary for remyelination by recruiting reparative glia and mediating signaling that promotes OPC differentiation/maturation. In response to demyelination, TREM2 is required for phagocytosis of large volumes of myelin debris. In addition to lysosomal regulation, we show TREM2 can modify the ER stress response, even prior to overt myelin debris, that prevents lipid accumulation and microglial dysfunction. These data support a role for Trem2-dependent interactions in age-related myelin degeneration and suggest a basis for how early dysfunctional microglia could contribute to disease pathology through insufficent repair, defective phagocytosis, and the ER stress response.

Entangled biphoton generation in the myelin sheath.

Consciousness within the brain hinges on the synchronized activities of millions of neurons, but the mechanism responsible for orchestrating such synchronization remains elusive. In this study we employ cavity quantum electrodynamics to explore entangled biphoton generation through cascade emission in the vibration spectrum of C-H bonds within the lipid molecules' tails. The results indicate that the cylindrical cavity formed by a myelin sheath can facilitate spontaneous photon emission from the vibrational modes and generate a significant number of entangled photon pairs. The abundance of C-H bond vibration units in neurons can therefore serve as a source of quantum entanglement resources for the nervous system. These findings may offer insight into the brain's ability to leverage these resources for quantum information transfer, thereby elucidating a potential source for the synchronized activity of neurons.

Axonal neurotransmitter release in the regulation of myelination.

Myelination of axons is a key determinant of fast action potential propagation, axonal health and circuit function. Previously considered a static structure, it is now clear that myelin is dynamically regulated in response to neuronal activity in the central nervous system (CNS). However, how activity-dependent signals are conveyed to oligodendrocytes remains unclear. Here, we review the potential mechanisms by which neurons could communicate changing activity levels to myelin, with a focus on the accumulating body of evidence to support activity-dependent vesicular signalling directly onto myelin sheaths. We discuss recent in vivo findings of activity-dependent fusion of neurotransmitter vesicles from non-synaptic axonal sites, and how modulation of this vesicular fusion regulates the stability and growth of myelin sheaths. We also consider the potential mechanisms by which myelin could sense and respond to axon-derived signals to initiate remodelling, and the relevance of these adaptations for circuit function. We propose that axonal vesicular signalling represents an important and underappreciated mode of communication by which neurons can transmit activity-regulated signals to myelinating oligodendrocytes and, potentially, more broadly to other cell types in the CNS.

Palmitoylation regulates myelination by modulating the ZDHHC3-Cadm4 axis in the central nervous system.

The downregulation of Cadm4 (Cell adhesion molecular 4) is a prominent feature in demyelination diseases, yet, the underlying molecular mechanism remains elusive. Here, we reveal that Cadm4 undergoes specific palmitoylation at cysteine-347 (C347), which is crucial for its stable localization on the plasma membrane (PM). Mutation of C347 to alanine (C347A), blocking palmitoylation, causes Cadm4 internalization from the PM and subsequent degradation. In vivo experiments introducing the C347A mutation (Cadm4-KI) lead to severe myelin abnormalities in the central nervous system (CNS), characterized by loss, demyelination, and hypermyelination. We further identify ZDHHC3 (Zinc finger DHHC-type palmitoyltransferase 3) as the enzyme responsible for catalyzing Cadm4 palmitoylation. Depletion of ZDHHC3 reduces Cadm4 palmitoylation and diminishes its PM localization. Remarkably, genetic deletion of ZDHHC3 results in decreased Cadm4 palmitoylation and defects in CNS myelination, phenocopying the Cadm4-KI mouse model. Consequently, altered Cadm4 palmitoylation impairs neuronal transmission and cognitive behaviors in both Cadm4-KI and ZDHHC3 knockout mice. Importantly, attenuated ZDHHC3-Cadm4 signaling significantly influences neuroinflammation in diverse demyelination diseases. Mechanistically, we demonstrate the predominant expression of Cadm4 in the oligodendrocyte lineage and its potential role in modulating cell differentiation via the WNT-ß-Catenin pathway. Together, our findings propose that dysregulated ZDHHC3-Cadm4 signaling contributes to myelin abnormalities, suggesting a common pathological mechanism underlying demyelination diseases associated with neuroinflammation.

Stem and progenitor cell-based therapy of myelin disorders.

Much of clinical neurology is concerned with diseases of-or involving-the brain's subcortical white matter. Common to these disorders is the loss of myelin, reflecting the elimination or dysfunction of oligodendrocytes and fibrous astrocytes. As such, the introduction of glial progenitor cells, which can give rise to new oligodendrocytes and astrocytes alike, may be a feasible strategy for treating a broad variety of conditions in which white matter loss is causally involved. This review first covers the sourcing and production of human glial progenitor cells, and the preclinical evidence for their efficacy in achieving myelin restoration in vivo. It then discusses both pediatric and adult disease targets for which transplanted glial progenitors may prove of therapeutic value, those challenges that remain in the clinical application of a glial cell replacement strategy, and the clinical endpoints by which the efficacy of this approach may be assessed.

Dysregulated miR-124 mediates impaired social memory behavior caused by paternal early social isolation.

Early social isolation (SI) leads to various abnormalities in emotion and behavior during adulthood. However, the negative impact of SI on offspring remains unclear. This study has discovered that paternal early SI causes social memory deficits and anxiety-like behavior in F1 young adult mice, with alterations of myelin and synapses in the medial prefrontal cortex (mPFC). The 2-week SI in the F1 progeny exacerbates social memory impairment and hypomyelination in the mPFC. Furthermore, the down-regulation of miR-124, a key inhibitor of myelinogenesis, or over-expression of its target gene Nr4a1 in the mPFC of the F1 mice improves social interaction ability and enhances oligodendrocyte maturation and myelin formation. Mechanistically, elevated levels of miR-124 in the sperm of paternal SI mice are transmitted epigenetically to offspring, altering the expression levels of miR-124/Nr4a1/glucocorticoid receptors in mPFC oligodendrocytes. This, in turn, impedes the establishment of myelinogenesis-dependent social behavior. This study unveils a novel mechanism through which miR-124 mediates the intergenerational effects of early isolation stress, ultimately impairing the establishment of social behavior and neurodevelopment.

Inherited white matter disorders: Hypomyelination (myelin disorders).

Hypomyelinating leukodystrophies are a subset of genetic white matter diseases characterized by insufficient myelin deposition during development. MRI patterns are used to identify hypomyelinating disorders, and genetic testing is used to determine the causal genes implicated in individual disease forms. Clinical course can range from severe, with patients manifesting neurologic symptoms in infancy or early childhood, to mild, with onset in adolescence or adulthood. This chapter discusses the most common hypomyelinating leukodystrophies, including X-linked Pelizaeus-Merzbacher disease and other PLP1-related disorders, autosomal recessive Pelizaeus-Merzbacher-like disease, and POLR3-related leukodystrophy. PLP1-related disorders are caused by hemizygous pathogenic variants in the proteolipid protein 1 (PLP1) gene, and encompass classic Pelizaeus-Merzbacher disease, the severe connatal form, PLP1-null syndrome, spastic paraplegia type 2, and hypomyelination of early myelinating structures. Pelizaeus-Merzbacher-like disease presents a similar clinical picture to Pelizaeus-Merzbacher disease, however, it is caused by biallelic pathogenic variants in the GJC2 gene, which encodes for the gap junction protein Connexin-47. POLR3-related leukodystrophy, or 4H leukodystrophy (hypomyelination, hypodontia, and hypogonadotropic hypogonadism), is caused by biallelic pathogenic variants in genes encoding specific subunits of the transcription enzyme RNA polymerase III. In this chapter, the clinical features, disease pathophysiology and genetics, imaging patterns, as well as supportive and future therapies are discussed for each disorder.

Rare forms of hypomyelination and delayed myelination.

Hypomyelination is defined by the evidence of an unchanged pattern of deficient myelination on two MRIs performed at least 6 months apart in a child older than 1 year. When the temporal criteria are not fulfilled, and the follow-up MRI shows a progression of the myelination even if still not adequate for age, hypomyelination is excluded and the pattern is instead consistent with delayed myelination. This can be mild and nonspecific in some cases, while in other cases there is a severe delay that in the first disease stages could be difficult to differentiate from hypomyelination. In hypomyelinating leukodystrophies, hypomyelination is due to a primary impairment of myelin deposition, such as in Pelizaeus Merzabcher disease. Conversely, myelin lack is secondary, often to primary neuronal disorders, in delayed myelination and some condition with hypomyelination. Overall, the group of inherited white matter disorders with abnormal myelination has expanded significantly during the past 20 years. Many of these disorders have only recently been described, for many of them only a few patients have been reported and this contributes to make challenging the diagnostic process and the interpretation of Next Generation Sequencing results. In this chapter, we review the clinical and radiologic features of rare and lesser known forms of hypomyelination and delayed myelination not mentioned in other chapters of this handbook.

Astrocyte-derived clusterin disrupts glial physiology to obstruct remyelination in mouse models of demyelinating diseases.

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models.

An anti-aging vaccine: BCG turns back the clock on remyelination failure.

Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.

Atlas-based assessment of hypomyelination: Quantitative MRI in Pelizaeus-Merzbacher disease.

Pelizaeus-Merzbacher disease (PMD) is a rare childhood hypomyelinating leukodystrophy. Quantification of the pronounced myelin deficit and delineation of subtle myelination processes are of high clinical interest. Quantitative magnetic resonance imaging (qMRI) techniques can provide in vivo insights into myelination status, its spatial distribution, and dynamics during brain maturation. They may serve as potential biomarkers to assess the efficacy of myelin-modulating therapies. However, registration techniques for image quantification and statistical comparison of affected pediatric brains, especially those of low or deviant image tissue contrast, with healthy controls are not yet established. This study aimed first to develop and compare postprocessing pipelines for atlas-based quantification of qMRI data in pediatric patients with PMD and evaluate their registration accuracy. Second, to apply an optimized pipeline to investigate spatial myelin deficiency using myelin water imaging (MWI) data from patients with PMD and healthy controls. This retrospective single-center study included five patients with PMD (mean age, 6 years ± 3.8) who underwent conventional brain MRI and diffusion tensor imaging (DTI), with MWI data available for a subset of patients. Three methods of registering PMD images to a pediatric template were investigated. These were based on (a) T1-weighted (T1w) images, (b) fractional anisotropy (FA) maps, and (c) a combination of T1w, T2-weighted, and FA images in a multimodal approach. Registration accuracy was determined by visual inspection and calculated using the structural similarity index method (SSIM). SSIM values for the registration approaches were compared using a t test. Myelin water fraction (MWF) was quantified from MWI data as an assessment of relative myelination. Mean MWF was obtained from two PMDs (mean age, 3.1 years ± 0.3) within four major white matter (WM) pathways of a pediatric atlas and compared to seven healthy controls (mean age, 3 years ± 0.2) using a Mann-Whitney U test. Our results show that visual registration accuracy estimation and computed SSIM were highest for FA-based registration, followed by multimodal, and T1w-based registration (SSIMFA = 0.67 ± 0.04 vs. SSIMmultimodal = 0.60 ± 0.03 vs. SSIMT1 = 0.40 ± 0.14). Mean MWF of patients with PMD within the WM pathways was significantly lower than in healthy controls MWFPMD = 0.0267 ± 0.021 vs. MWFcontrols = 0.1299 ± 0.039. Specifically, MWF was measurable in brain structures known to be myelinated at birth (brainstem) or postnatally (projection fibers) but was scarcely detectable in other brain regions (commissural and association fibers). Taken together, our results indicate that registration accuracy was highest with an FA-based registration pipeline, providing an alternative to conventional T1w-based registration approaches in the case of hypomyelinating leukodystrophies missing normative intrinsic tissue contrasts. The applied atlas-based analysis of MWF data revealed that the extent of spatial myelin deficiency in patients with PMD was most pronounced in commissural and association and to a lesser degree in brainstem and projection pathways.

Glial cholesterol redistribution in hypoxic injury in vitro influences oligodendrocyte maturation and myelination.

Hypoxic insult to the fetal brain causes loss of vulnerable premyelinating oligodendrocytes and arrested oligodendrocyte differentiation. Astrocytes influence oligodendrocyte differentiation and the astrocytic response to hypoxia could affect oligodendrocyte maturation under hypoxia. To identify pathways by which astrocytes influence oligodendroglial maturation in hypoxic injury, human fetal neural stem cell-derived astrocytes were exposed to 0.2 % oxygen for 48 hours. Transcriptomic analysis revealed the upregulation of the cholesterol-biosynthesis pathway in hypoxia-exposed astrocytes. Hypoxia-exposed primary astrocytes and astrocytic cell line (SVG) showed increased expression of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), squalene epoxidase (SQLE), apolipoprotein E (apoE) and ATP-binding cassette transporter 1 (ABCA1) on qPCR and Western blot. Hypoxic SVG also showed increased cholesterol content in cells and culture supernatants and increased cell surface expression of ABCA1. Interestingly hypoxia-exposed premyelinating oligodendrocytes (Mo3.13) showed reduced cholesterol along with decreased expression of HMGCR and SQLE on qPCR and Western blot. Exogenous cholesterol increased the differentiation of Mo3.13 as measured by increased expression of myelin basic protein (MBP) on flow cytometry. Hypoxia exposure resulted in increased cholesterol transport from astrocytes to oligodendrocytes in cocultures with BODIPY-cholesterol labelled SVG and membrane-labelled Mo3.13. As exogenous cholesterol enhanced oligodendrocyte differentiation, our findings indicate that increased cholesterol synthesis by astrocytes and transport to oligodendrocytes could supplement oligodendroglial maturation in conditions of hypoxic brain injury in neonates.

Glaucoma, More than Meets the Eye: Patterns of Demyelination Revealed in Human Postmortem Glaucomatous Optic Nerve.

Glaucoma is a neurodegenerative disease affecting millions worldwide, characterised by retinal ganglion cell (RGC) degeneration which leads to blindness in more advanced cases. Although the pathogenesis and underlying mechanisms of glaucoma are not fully understood, there are theories that hint at demyelination playing a role in the disease process. Demyelination, or the degeneration of the myelin sheath surrounding axons, has been found in previous studies using animal models of glaucoma and clinical assessments of glaucoma patients. However, this has not been fully realised or quantified in glaucoma patients. Utilising postmortem optic nerve samples from glaucoma and healthy subjects, various immunohistochemical and morphological assessments were performed to determine the extent, if any, of demyelination in glaucomatous optic nerves. Our findings revealed that alongside nerve shrinkage and degeneration of nerve tissue fascicles, there were significantly less myelin proteins, specifically myelin basic protein (MBP), in glaucoma optic nerves. Additionally, the loss of MBP was correlated with decreased oligodendrocyte (OLG) precursors and increasing glial activity. This further supports previous evidence that demyelination may be a secondary degenerative process associated with glaucoma disease progression. Not only do these results provide evidence for potential disease mechanisms, but this is also the first study to quantify optic nerve demyelination in glaucoma postmortem tissue.

Zinc-Finger Protein ZFP488 Regulates the Timing of Oligodendrocyte Myelination and Remyelination.

Oligodendrocyte myelination and remyelination after injury are intricately regulated by various intrinsic and extrinsic factors, including transcriptional regulators. Among these, the zinc-finger protein ZFP488 is an oligodendrocyte-enriched transcriptional regulator that promotes oligodendrocyte differentiation in the developing neural tube and in oligodendroglial cell lines. However, the specific in vivo genetic requirements for ZFP488 during oligodendrocyte development and remyelination have not been defined. To address this gap, we generated a lineage-traceable ZFP488 knock-out mouse line, wherein an H2b-GFP reporter replaces the ZFP488-coding region. Using these mice of either sex, we examined the dynamics of ZFP488 expression from the endogenous promoter in the developing central nervous system (CNS). We observed a unique expression pattern in the oligodendrocyte lineage, with ZFP488 expression particularly enriched in differentiated oligodendrocytes. ZFP488 loss resulted in delayed myelination in the developing CNS and impaired remyelination after demyelinating injury in the brain. Integrated transcriptomic and genomic profiling further revealed that ZFP488 loss decreased the expression of myelination-associated genes but not oligodendrocyte progenitor-associated genes, suggesting that ZFP488 serves as a positive regulator of myelination by regulating maturation programs. Thus, our genetic loss-of-function study revealed that ZFP488 regulates a stage-dependent differentiation program that controls the timing of CNS myelination and remyelination.

Water phase transition and signal nulling in 3D dual-echo adiabatic inversion-recovery UTE (IR-UTE) imaging of myelin.

PURPOSE: The semisolid myelin sheath has very fast transverse relaxation and is invisible to conventional MRI sequences. UTE sequences can detect signal from myelin. The major challenge is the concurrent detection of various water components. METHODS: The inversion recovery (IR)-based UTE (IR-UTE) sequence employs an adiabatic inversion pulse to invert and suppress water magnetizations. TI plays a key role in water suppression, with negative water magnetizations (negative phase) before the null point and positive water magnetizations (positive phase) after the null point. A series of dual-echo IR-UTE images were acquired with different TIs to detect water phase transition. The effects of TR in phase transition and water suppression were also investigated using a relatively long TR of 500 ms and a short TR of 106 ms. The water phase transition in dual-echo IR-UTE imaging of myelin was investigated in five ex vivo and five in vivo human brains. RESULTS: An apparent phase transition was observed in the second echo at the water signal null point, where the myelin signal was selectively detected by the UTE data acquisition at the optimal TI. The water phase transition point varied significantly across the brain when the long TR of 500 ms was used, whereas the convergence of TIs was observed when the short TR of 106 ms was used. CONCLUSION: The results suggest that the IR-UTE sequence with a short TR allows uniform inversion and nulling of water magnetizations, thereby providing volumetric imaging of myelin.

Macrophage-mediated myelin recycling fuels brain cancer malignancy.

Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.

Oligodendrocytes and myelin limit neuronal plasticity in visual cortex.

Developmental myelination is a protracted process in the mammalian brain1. One theory for why oligodendrocytes mature so slowly posits that myelination may stabilize neuronal circuits and temper neuronal plasticity as animals age2-4. We tested this theory in the visual cortex, which has a well-defined critical period for experience-dependent neuronal plasticity5. During adolescence, visual experience modulated the rate of oligodendrocyte maturation in visual cortex. To determine whether oligodendrocyte maturation in turn regulates neuronal plasticity, we genetically blocked oligodendrocyte differentiation and myelination in adolescent mice. In adult mice lacking adolescent oligodendrogenesis, a brief period of monocular deprivation led to a significant decrease in visual cortex responses to the deprived eye, reminiscent of the plasticity normally restricted to adolescence. This enhanced functional plasticity was accompanied by a greater turnover of dendritic spines and coordinated reductions in spine size following deprivation. Furthermore, inhibitory synaptic transmission, which gates experience-dependent plasticity at the circuit level, was diminished in the absence of adolescent oligodendrogenesis. These results establish a critical role for oligodendrocytes in shaping the maturation and stabilization of cortical circuits and support the concept of developmental myelination acting as a functional brake on neuronal plasticity.