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The X-Linked Intellectual Disability gene, ZDHHC9, is important for oligodendrocyte maturation and myelin formation

ABSTRACT: Two percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme, ZDHHC9. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a disruption of white matter integrity. We demonstrated that ablation of Zdhhc9 in mice substantially impairs the maturation of oligodendrocytes, resulting in fewer mature, myelinating oligodendrocytes, higher numbers of oligodendrocyte progenitor cells and a decrease in the density of myelinated axons. Ultrastructural analysis of the remaining myelinated axons in the corpus callosum revealed further disruptions in myelin integrity. RNA sequencing and proteomic analyses revealed a concomitant decrease in the expression of genes and proteins involved in lipid metabolism, cholesterol synthesis and myelin compaction. These results reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte differentiation and myelinogenesis and provide mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

ORGANISM(S): Mus musculus

PROVIDER: GSE236665 | GEO | 2023/08/21

REPOSITORIES: GEO

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The X-Linked Intellectual Disability gene, ZDHHC9, is important for oligodendrocyte maturation and myelin formation

Project description:Two percent of all patients with X-linked intellectual disability (XLID) exhibit loss-of-function mutations in the palmitoylating enzyme, ZDHHC91,2. One of the main anatomical deficits observed in these patients is a decrease in corpus callosum volume and a disruption of white matter integrity. We demonstrated that ablation of Zdhhc9 in mice substantially impairs the maturation of ligodendrocytes, resulting in fewer mature, myelinating oligodendrocytes, higher numbers of oligodendrocyte progenitor cells and a decrease in the density of myelinated axons. Ultrastructural analysis of the remaining myelinated axons in the corpus callosum revealed further disruptions in myelin integrity. RNA sequencing and proteomic analyses revealed a concomitant decrease in the expression of genes and proteins involved in lipid metabolism, cholesterol synthesis and myelin compaction. These results reveal a previously underappreciated and fundamental role for ZDHHC9 and protein palmitoylation in regulating oligodendrocyte differentiation and myelinogenesis and provide mechanistic insights into the deficits observed in white matter volume in patients with mutations in ZDHHC9.

2023-06-30 | MSV000092318 | MassIVE

Transcriptomic analyses of astrocyte heterogeneity within white matter tracts

Project description:Astrocytes are broadly categorized as protoplasmic or fibrous, with the former localized to synaptically dense gray matter regions and the latter associated with axons in the white matter. Much of what we know about astrocyte form and function is derived from the study of protoplasmic astrocytes, whereas fibrous astrocytes remain relatively unexplored. We investigated the transcriptome of uninjured fibrous astrocytes in the mouse from three regions: unmyelinated optic nerve head (ONH), myelinated optic nerve proper (ONP), and corpus callosum (CC).

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PAD2-mediated citrullination contributes to efficient oligodendrocyte differentiation and myelination

Project description:Citrullination, the deimination of arginine residues into citrulline, has been implicated in the aetiology of several diseases. In multiple sclerosis (MS), citrullination is thought to be a major driver of pathology, through hypercitrullination and destabilization of myelin. As such, inhibition of citrullination has been suggested as a therapeutical strategy for MS. Here we show that citrullination by peptidylarginine deiminase 2 (PADI2) is in contrast required for normal oligodendrocyte differentiation, myelination and motor function. We identify several targets for PADI2, including not only myelin-related proteins, but also several chromatin-associated proteins, implicating PADI2 in epigenetic regulation. Accordingly, we observe that PADI2 inhibition and its knockdown affect chromatin accessibility and prevent the upregulation of genes involved in oligodendrocyte differentiation. Moreover, mice lacking PADI2, display motoric dysfunction and a decreased number of myelinated axons in the corpus callosum. Our study demonstrates that citrullination is required for oligodendrocyte lineage progression and myelination and thus its targeted activation in the oligodendrocyte lineage might be beneficial in the context of remyelination in diseases as MS.

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Ferroptosis in oligodendrocyte progenitor cells mediates white matter injury after hemorrhagic stroke

Project description:Oligodendrocyte progenitor cells (OPCs) differentiate to myelin-producing mature oligodendrocytes and enwrap growing or demyelinated axons during development and post central nervous diseases. Failure of remyelination due to cell death or undifferentiation of OPC contributes to severe neurologic deficits and motor dysfunction. However, how to prevent the cell death of OPCs is still poorly understood, especially in hemorrhagic diseases. In this current study, we injected autologous blood into the mouse lateral ventricular to study the hemorrhage induced OPC cell death in vivo. The integrity of the myelin sheath of the corpus callosum was disrupted post intraventricular hemorrhage (IVH) assessed by using magnetic resonance imaging, immunostaining, and transmission electron microscopy. Consistent with the severe demethylation, we observed massive cell death of oligodendrocyte lineages in the periventricular area. In addition, we found that ferroptosis is the major cell death form in Hemin-induced OPC death by using RNA-seq analysis, and the mechanism was glutathione peroxidase 4 (GPx4) expression and activity reduction-resulted lipid peroxide accumulation. Furthermore, inhibition of ferroptosis rescued OPC cell death in vitro, and in vivo attenuated IVH-induced white matter injury and promoted recovery of neurological function. These data demonstrate that ferroptosis is an essential form of OPC cell death in hemorrhagic stroke, and rescuing ferroptotic OPCs could serve as a therapeutic target for stroke and related diseases.

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Unique microglia expression profile in developing white matter.

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2020-04-10 | GSE132688 | GEO

BRG1 programs PRC2-complex repression and controls oligodendrocyte differentiation and remyelination

Project description:Mutations in Brg1 can cause Coffin-Siris syndrome, where a patient had white matter defects and partial agenesis of the corpus callosum; however, Brg1 functions in CNS myelination and remyelination is unsure. We show that PDGFRa expressed prior than NG2, depletion of Brg1 at PDGFRα+ OPC leads to OPC differentiation restriction and myelin defects, also, Brg1 is critical for oligodendrocyte remyelination. Genomic occupancy and transcriptome analyses indicate that Brg1 promotes H3K27me3 and neuronal genes. Thus our findings reveal that Brg1 is a critical epigenetic programmer of CNS myelination and repair through recruiting H3K27me3 and neuronal genes, suggesting potential strategies of therapeutic intervention for Brg1-associated white matter defects.

2024-03-25 | GSE205236 | GEO

Opposite roles for astrocytes in developmental myelination and early myelin repair

Project description:Understanding the regulation of oligodendrocyte development and myelination in the central nervous system (CNS) is essential, not only to facilitate myelin repair but also to define the role of oligodendrocytes in maintaining axonal integrity. In vitro studies have implicated astrocytes in influencing multiple aspects of oligodendrocytes and their precursors, however the in vivo role of astrocytes in myelination and myelin repair remain poorly defined. We show that astrocyte ablation during postnatal spinal cord development resulted in a concomitant delay in myelination, demonstrating a critical role for astrocytes in promoting developmental myelination. By contrast, in the adult CNS, localized ablation of astrocytes 2 days after a demyelinating insult resulted in increased numbers of oligodendrocytes and accelerated remyelination in both the spinal cord and the corpus callosum. Microarray analysis reveals astrocytic NF-kB signaling pathway as a major contributor to pathological events occurring after demyelination. We suggest that the localized functions of astrocytes are fundamentally different during developmental myelination and myelin repair. Astrocytes are critical for developmental myelination, however in a demyelinating environment they are detrimental to myelin repair.

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CD8+ T cells induce interferon-responsive oligodendrocytes during white matter aging

Project description:A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. Here, we found age-related alterations of oligodendrocytes with a reduction of total oligodendrocyte density in the aging murine white matter. Using single-cell RNA sequencing, we identify interferon-responsive oligodendrocytes, which localize in proximity of CD8+ T cells in the aging white matter. Absence of functional lymphocytes decreased oligodendrocyte reactivity and rescued oligodendrocyte loss, while T-cell checkpoint inhibition worsened the aging effect. In addition, we identified a subpopulation of immune cell dependent interferon-responsive microglia in the aging white matter, and co-culture experiments revealed that interferon- activated microglia triggered oligodendrocytes cell death. In summary, we provide evidence that T cells induced interferon-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

2022-09-13 | GSE202579 | GEO

Single-cell RNA-Seq of mice treated with lysolecithin at baseline, 5 days post lesioning, 14 days post lesioning and 28 days post-lesioning, 3-4 months old

Project description:Here we studied the transcriptional changes in the oligodendrocyte lineage cells of corpus callosum in and around the region lesioned by injection of lysolecithin by using unbiased single cell RNA-seq. We identified three distinct activation states of oligodendrocytes, termed disease associated oligodendrocytes and associated gene expression signatures. We observed increases in proportion of disease associated oligodendrocytes along different timepoints post lysolecithin treatment. This study will provide resources to study the molecular mechanisms driving de/remyelination induced by lysolecithin.

2022-08-23 | GSE182846 | GEO

Gene expression changes in the periventricular white matter of neonatal piglets at a defined 48h time point following a hypoxic-ischemic insult: a comparison of piglets left untreated and those treated with a remote post-conditioning stimulus applied to the hind leg immediately after the insult.

Project description:Remote ischemic postconditioning (RIPostC) is a promising therapeutic intervention whereby brief episodes of ischemia/reperfusion of one organ (limb) mitigate damage in another organ (brain) that has experienced severe hypoxia-ischemia. 16 Large White newborn female piglets were exposed to a tightly controlled hypoxic-ischemic insult using magnetic resonance spectroscopy (MRS) biomarkers. After hypoxia-ischemia (HI), piglets were randomized to: (i) no intervention (nâ=â8); (ii) RIPostC â with four, 10-min cycles of bilateral lower limb ischemia/reperfusion immediately after HI (nâ=â8). Piglets in the remote post-conditioned group exhibited a reduction in white matter proton MRS lactate/N acetyl aspartate and increased whole brain phosphorus-31 MRS ATP over the 48âh after hypoxia-ischemia. Cell death (apoptosis) was reduced with RIPostC in the periventricular white matter, internal capsule and corpus callosum. There was also reduced microglial activation in corpus callosum and more surviving oligodendrocytes in corpus callosum and periventricular white matter. Our results demonstrate changes in the expression of 74 genes in the periventricular white matter 63 were down regulated and 11 were upregulated, that accompany the reductions in cell death and microglial activation seen following a remote post conditioning stimulus at a single 48h time point. (significance was calculated at p<0.05, one way ANOVA, Mann-Whitney unpaired, noe were found to be significant following a Benjamini-Hochberg FDR multipe testing correction). Many of these genes are thought to be important for the mediation of the neuroprotective effects of post-conditioning which suggests its genomic effects may persist for 48h. A full description of this work can be accessed at doi: 10.1177/0271678X15608862.

2016-09-21 | E-MTAB-5125 | biostudies-arrayexpress

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