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Gsta4 restricts apoptosis in differentiating adult oligodendrocytes via Fas/Casp8/Bid-axis during homeostasis and remyelination

ABSTRACT: Arrest of oligodendrocyte (OL) differentiation and remyelination following myelin damage in Multiple Sclerosis (MS) are associated with disease progression but the underlying mechanism are elusive. We show that Glutathione S-transferase 4α (Gsta4) is highly expressed during adult OL differentiation and that its loss prevents differentiation into myelinating OLs. Also, Gsta4 appeared to be a novel target for Clemastine, in clinical trial for MS. Over-expression of Gsta4 reduced the expression of Fas and activity along the mitochondria-associated Casp8/Bid-axis in adult pre-OLs from the corpus callosum, together promoting enhanced pre-OL survival during differentiation. The Gsta4-mediated input on apoptosis during adult OL differentiation was further verified in the LPC and EAE model, where Casp8 were reduced in pre-OLs with high Gsta4 expression in an immune response-independent fashion. Our results place Gsta4 as a key regulator of intrinsic mechanisms beneficial for OL differentiation and remyelination, and as a possible target for future MS therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE154922 | GEO | 2020/07/23

REPOSITORIES: GEO

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Respiratory infection with influenza A virus delays remyelination and alters oligodendrocyte metabolism.

Project description:Peripheral viral infection disrupts oligodendrocyte homeostasis such that endogenous remyelination may be affected. Here, we demonstrate that influenza A virus infection perpetuated a demyelination- and disease-associated oligodendrocyte (OL) phenotype following cuprizone-induced demyelination that resulted in delayed OL maturation and remyelination in the prefrontal cortex. Furthermore, we assessed cellular metabolism ex-vivo, and found that infection altered brain OL and microglia metabolism in a manner that opposed the metabolic profile induced by remyelination. Specifically, infection increased glycolytic capacity of OLs and microglia, an effect that was recapitulated by LPS stimulation of mixed glia cultures. In contrast, mitochondrial respiration was increased in OLs during remyelination, which was similarly observed in OLs of myelinating P14 mice compared to adult and aged mice. Collectively, our data indicate that respiratory viral infection is capable of suppressing remyelination, and suggest that metabolic dysfunction of OLs is implicated in remyelination impairment.

2024-08-14 | GSE253710 | GEO

Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [RNA-seq II]

Project description:Impairment of oligodendrocyte (OL) myelinogenic potential, rather than inability of oligodendrocyte precursors to differentiate, is implicated in remyelination failure in demyelinating diseases such as multiple sclerosis. However, the mechanisms underlying myelinogenesis and age-related decline in remyelination remain elusive. Here, we identify a mature-OL-active transcriptional regulator Dor as a critical mediator of CNS myelination and remyelination. Genomic occupancy and transcriptomic analyses revealed that Dor interacts with Sox10 and targets the enhancers of myelinogenesis-regulatory genes including a newly identified OL-enriched nuclear factor Prr18 required for OL maturation. Metabolomic profiling showed that Dor is critical for alpha-ketoglutarate (alpha-KG) production and lipid biosynthesis. Supplementation with alpha-KG enhanced lipid biosynthesis and restored OL maturation defects in Dor-mutant mice while reversing the age-associated decline in remyelination efficiency and memory deficits in aging mice. Thus, our findings connect the OL-active Dor regulatory activity to alpha-KG-mediated lipid metabolism in mature OLs to thereby facilitate myelin production and remyelination.

2024-07-05 | GSE261859 | GEO

Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [CUT&Tag]

2024-07-05 | GSE233591 | GEO

Dor regulates alpha-KG metabolic pathways in mature oligodendrocytes to enhance myelination and reverse age-related remyelination decline [RNA-seq]

2024-07-05 | GSE233592 | GEO

Loss of miR-145 promotes remyelination and functional recovery in a model of chronic centrel demyelination

Project description:Strategies for treating progressive multiple sclerosis (MS) remain limited. Here, we found that miR-145-5p is overabundant uniquely in chronic lesion tissues from secondary progressive MS patients. We induced both acute and chronic demyelination in miR-145 knockout mice to determine its contributions to remyelination failure. Following acute demyelination, no advantage to miR-145 loss could be detected. However, after chronic demyelination, animals with miR-145 loss demonstrated increased remyelination and functional recovery, coincident with altered presence of astrocytes and microglia within the corpus callosum relative to wild-type animals. This improved response in miR-145 knockout animals coincided with a pathological upregulation of miR-145-5p in wild-type animals with chronic cuprizone exposure, paralleling human chronic lesions. Furthermore, miR-145 overexpression specifically in oligodendrocytes (OLs) severely stunted differentiation and negatively impacted survival. RNAseq analysis showed altered transcriptome in these cells with downregulated major pathways involved in myelination. Our data suggest that pathological accumulation of miR-145-5p is a distinctive feature of chronic demyelination and is strongly implicated in the failure of remyelination, possibly due to the inhibition of OL differentiation together with alterations in other glial cells. This is mirrored in chronic MS lesions, and thus miR-145-5p serves as a potential relevant therapeutic target in progressive forms of MS.

2024-05-31 | GSE268808 | GEO

*Possible corruption in count data files-update in progress* Disease-specific oligodendrocyte lineage cells express immunoprotective and adaptive immunity genes in multiple sclerosis

Project description:Single-cell RNA-seq of a mouse model of MS uncovers new oligodendrocyte populations, putative disease markers and suggests new mechanisms underlying the pathogenesis of disease. In Multiple Sclerosis (MS), oligodendrocytes (OLs) are damaged during an immune system attack targeting myelin. It remains unclear how different OL lineage cells respond to inflammatory autoimmune demyelination in MS. We performed single-cell transcriptomics analysis of OL lineage cells from the spinal cord of mice induced with experimental autoimmune encephalomyelitis (EAE), which mimics certain aspects of MS. We found unique OLs and OL precursor cells (OPCs) in EAE, including populations expressing genes involved in antigen processing and presentation via major histocompatibility complex (MHC) Class I and II, but also in immunoprotection. We further uncovered several genes specifically alternatively spliced in OL lineage cells in EAE, including Mbp, Mobp and Pdgfa. Strikingly, we identified a substantial number of genes known to be susceptibility genes for MS, so far mainly associated with immune cells in the context of this disease, to be expressed in the OL lineage cells. Finally, we found that disease-specific oligodendroglia are present in human MS brains. Our results suggest that OL and OPCs are not passive targets but instead active immunomodulators in MS. The disease-specific OL lineage cells, for which we identify several biomarkers, may represent novel direct targets for immunomodulatory therapeutic approaches in MS.

2018-08-25 | GSE113973 | GEO

Altered oligodendrocyte heterogeneity in Multiple sclerosis.

Project description:Oligodendrocyte (OL) pathology is increasingly implicated in neurodegenerative diseases, as they are involved in metabolic support of axons and functional cross-talk with other brain cells. Rodent OLs are heterogeneous, with developmental and biological differences, but the extent of heterogeneity in the normal human brain and its contribution to any changes of disease remains unknown. Here we performed single nuclei RNA-sequencing (snRNA-seq) from white matter (WM) areas of post mortem human brain both in control (Ctr) and multiple sclerosis (MS) patients. We identified several sub-clusters of oligodendroglia in the Ctr human WM, some similar to those in mouse, and defined new markers for these. Strikingly, some of these sub-clusters were under-represented in MS tissue, while others were more prevalent than in controls. There was a lack of OL precursor cells (OPCs) and OLs in an intermediate stage of differentiation in MS lesions and in normal appearing white matter (NAWM), suggesting either depletion by the disease or by a regenerative response. The differences in mature OL sub-clusters indicate different functional states of OLs in MS tissue and, as this is similar in NAWM to lesions, that MS is a more diffuse brain disease than the focal demyelinating lesions suggest. We were also able to identify new markers of different MS lesion subtypes. Our findings of an altered heterogeneity of oligodendroglia in MS may have an important contribution to our understanding of disease progression and may alter therapeutic approaches to MS.

2019-01-23 | GSE118257 | GEO

microRNAs dysregulated in multiple sclerosis affect the differentiation of CG-4 cells, an oligodendrocyte progenitor cell line

Project description:Remyelination in multiple sclerosis (MS) is from the start of the disease imperfect, and strongly decreases with its progression, mainly due to the harm on oligodendrocyte progenitor cells (OPCs), causing neurodegeneration and resulting in irreversible neurological deficits. Therapeutic strategies promoting remyelination are still very preliminary and lack within the current treatment panel of MS. In a previous study we have identified 21 microRNAs dysregulated mostly in the CSF of relapsing and/or remitting MS patients. Here, we observed that among these, the majority of 13 transfected microRNA mimics decreased the differentiation of an OPC cell line called CG-4. Herein we support by RNA sequencing and independent RT-qPCR analyses that miR-33-3p, miR-34c-5p, miR-124-5p, and miR-145-5p impede OPC differentiation as evidenced by the downregulation of premyelinating oligodendrocyte (OL) (Tcf7l2, Cnp [except for miR-145-5p]) and mature OL (Plp1, Mbp, Mobp) markers, whereas only miR-214-3p promotes OPC differentiation. We further propose a comprehensive exploration of their change in cell fate through Gene Ontology enrichment analysis. We finally confirm by RT-qPCR analysis the downregulation of several predicted mRNA targets for each microRNA that possibly support their effect on OPC differentiation by very distinctive mechanisms, of which some are still unexplored in OPC/OL physiology. We hereby open new perspectives in the research on OPC differentiation and the pathophysiology of demyelination/remyelination, and possibly even in the research on new remyelinating therapeutic strategies in the scope of MS.

2024-02-07 | GSE244479 | GEO

Rapid differentiation of hiPSCs into functional oligodendrocytes using an OLIG2 synthetic modified messenger RNARapid differentiation of hiPSCs into functional oligodendrocytes using an OLIG2 synthetic modified messenger RNA

Project description:We show that a synthetic modified messenger RNA (smRNA)-based reprogramming method that leads to the generation of transgene-free OLs has been developed. An smRNA encoding a modified form of OLIG2, a key TF in OL development, in which the serine 147 phosphorylation site is replaced with alanine, OLIG2S147A, is designed to reprogram hiPSCs into OLs. We demonstrate that repeated administration of the smRNA encoding OLIG2 S147A lead to higher and more stable protein expression. Using the single-mutant OLIG2 smRNA morphogen, we establish a 6-day smRNA transfection protocol, and glial induction lead to rapid NG2+ OL progenitor cell (OPC) generation (> 70% purity) from hiPSC-derived neural progenitor cells (NPCs). The smRNA-induced NG2+ OPCs can mature into functional OLs in vitro and promote remyelination in vivo. Proteomic analysis of OLIG2-binding proteins indicates that OLIG2 is bound by the heat shock protein 70 (HSP70) complex. The HSP70 complex is bound more strongly to OLIG2 with the modified phosphorylation site than to wild-type OLIG2.

2023-03-10 | PXD036975 | Pride

Project description:Myelin destruction and oligodendrocyte (OL) death consequent to metabolic stress is a feature of CNS disorders across the age spectrum. Using cells derived from surgically resected tissue, we demonstrate that young (<age 5) pediatric-aged sample OLs are more resistant to in-vitro metabolic injury than fetal O4+ progenitor cells, but more susceptible to cell death and apoptosis than adult-derived OLs. Pediatric but not adult OLs show measurable levels of TUNEL+ cells, a feature of the fetal cell response. The ratio of anti- versus pro-apoptotic BCL-2 family genes are increased in adult versus pediatric (<age 5) mature OLs and in more mature OL lineage cells. Lysosomal gene expression was increased in adult and pediatric compared to fetal OL lineage cells. Cell death of OLs was increased by inhibiting pro-apoptotic BCL-2 gene and autophagy activity. These distinct age-related injury responses should be considered in designing therapies aimed at reducing myelin injury.

2020-12-31 | GSE160811 | GEO

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