Influenza infection disrupts oligodendrocyte homeostasis and alters the myelin lipidome in the adult mouse central nervous system.
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PROVIDER: PRJNA859688 | ENA |
REPOSITORIES: ENA
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Project description:The notion that myelin remains static during adulthood has been challenged in recent years, and it is increasingly recognized that myelin may be altered by physiological events occurring outside of the central nervous system resulting in changes to cognition and behavior. The consequences of influenza A virus infection on oligodendrocytes in the adult mouse were investigated. Transcriptomic analysis revealed global downregulation and subsequent recovery of oligodendrocyte-specific transcripts in response to peripheral viral infection. Infection neither affected myelin thickness nor oligodendrocyte survival in the mPFC but altered the oligodendrocyte proteome and increased a disease-specific marker associated with oligodendrocyte stress. Furthermore, shot-gun lipidomic analysis revealed that infection altered the lipid profile in the prefrontal cortex as well as in purified brain myelin. Finally, treatment with the CSF1R antagonist GW2580 suppressed glial activation and partially restored oligodendrocyte-specific transcripts to baseline levels during infection. Together, these findings show that peripheral immunological challenge altered oligodendrocyte physiology.
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Project description:Alzheimer’s disease (AD) is characterized not only by neuronal loss and synaptic dysfunction but also by emerging evidence of oligodendrocyte and myelin pathology. Amyloid-β (Aβ), a hallmark of AD, disrupts oligodendrocyte homeostasis through mechanisms that remain poorly understood. Here, we investigated the role of the myelin regulatory factor (MYRF), a transcription factor essential for oligodendrocyte maturation, in AD-related glial dysfunction. Using the 3xTg-AD mouse model, we observed aberrantly induced maturation dynamics and reduced oligodendrocyte lineage cell density at 12 months in the dentate gyrus, accompanied by increased MYRF expression. Interestingly, sustained MYRF overexpression was found to be toxic for oligodendrocytes in vitro. Moreover, in vitro and in vivo experiments further demonstrated that Aβ exposure elevates MYRF protein levels and enhances its transcriptional activity, pointing to post-translational regulation. Mechanistically, Aβ impaired GSK3-dependent phosphorylation and Fbxw7-mediated ubiquitination of MYRF, prolonging N-MYRF stability, an effect prevented by PKC inhibition in vitro. Intracerebroventricular infusion of PKC inhibitor Gö6983 normalized MYRF levels, restored oligodendrocyte populations and myelin integrity, and improved hippocampal-dependent spatial learning in 3xTg-AD mice, with locomotor activity and anxiety-like behavior remaining unaffected. Together, these findings identify MYRF dysregulation as a mechanistic link between Aβ/PKC signaling and oligodendrocyte pathology, and highlight PKC inhibition as a potential strategy to restore oligodendroglial function and cognition in AD.
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Project description:Failed regeneration of myelin around neuronal axons following central nervous system damage contributes to nerve dysfunction and clinical decline in various neurological conditions, for which there is an unmet therapeutic demand. Here, we show that interaction between glial cells – astrocytes and mature myelin-forming oligodendrocytes – is a critical determinant of remyelination. Using in vivo/ ex vivo/ in vitro rodent models and human brain lesion analyses, we discover that astrocytes support the survival of regenerating oligodendrocytes, via downregulation of the Nrf2 pathway associated with increased astrocytic cholesterol biosynthesis pathway activation. Remyelination fails following sustained astrocytic Nrf2 activation in focally-lesioned mice yet is restored by either cholesterol biosynthesis/efflux stimulation, or Nrf2 inhibition using the existing therapeutic Luteolin. We identify that astrocyte-oligodendrocyte interaction regulates remyelination, and reveal a drug strategy for central nervous system regeneration centred on targeting this interaction.
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Project description:Myelin is required for the function of neuronal axons in the central nervous system, yet the mechanisms supporting myelin health are unclear. Although central nervous system macrophages have been implicated, it is unknown which macrophage populations are involved and which aspects of myelin health they influence. Here, we show that resident microglia are critical for the maintenance of myelin health in adulthood in both mouse and human. We demonstrate that whereas microglia are dispensable for developmental myelin ensheathment, they are required for subsequent regulation of myelin growth and associated cognitive function, and for the preservation of myelin integrity by preventing its degeneration. We discovered that loss of myelin health in the absence of microglia is underpinned by the appearance of a myelinating oligodendrocyte subpopulation with altered lipid metabolism, regulated by a disruption of the TGFβ1-TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions where myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease.
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2016-06-24 | E-GEOD-78151 | biostudies-arrayexpress
Project description: Not available
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Project description:One way by which astrocytes modulate oligodendrocytes’ activity is by delivering neurotransmitters and leukemia inhibitory factor (Lif) in the medium that bind oligodendrocyte receptors. Most of these receptors are involved in intercellular Ca2+-signaling (ICS). However, not much is known about the interactions between myelination (MYE) and ICS genes and how astrocyte nearness modulates the oligodendrocyte genomic myelination fabric. We profiled the transcriptomes of immortalized oligodendrocyte precursor cells (Oli-neu) when cultured alone or co-cultured with cortical astrocytes. The astrocytes were plated in cell culture insert systems that did not allow formation of gap junction channels with oligodendrocytes but permitted exchange of soluble factors via the culture medium. Remarkably, astrocyte proximity induced a larger increase of the overall expression level and interlinkage of MYE genes than the differentiating 10d treatment with 1 mM dibutyryl cAMP that turns Oli-neu cells into myelin-associated glycoprotein-positive oligodendrocyte-like cells. Moreover, more MYE and ICS genes were turned on and fewer turned off by astrocyte proximity than by differentiating treatment. Lif receptor was up-regulated by astrocyte proximity but not by the differentiating treatment. We have identified the responsible transcriptomic networks by which the intercellular ICS gene web controls MYE gene web, with genes encoding the gap junction proteins (connexins, Cx) Cx29, Cx32 and Cx47 playing central roles. The novel Prominent Gene Analysis (that refines iteratively the functional webs to optimize the interconnectivity and expression stability of the associated genes) was used to select and rank the most relevant MYE and ICS genes and build the corresponding gene webs. Determine the modifications of the myelination transcriptome induced in Oli- neu control cells by differentiating treatment and proximity of cortical astrocytes. Four culture dishes of each of control, differentiated and in the astrocyte proximity Oli-neu cells were profiled using Duke mouse 30K and 36k oligonucleotide arrays in the "multiple yellow" hybrization design.
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Project description:Myelin is one of the most important features of the vertebrate nervous system, formed by glial cells. In the peripheral nervous system, Schwann cells produce myelin. While much is known about the molecules and processes involved in mammalian myelination, little is known about it in other vertebrate groups. In this study, we examined myelin development in the peripheral nerves of the turtle Trachemys scripta using qPCR, RNA sequencing, immunofluorescence, and TEM. Our findings indicate that in T. scripta, myelination begins during the late stages of embryonic development and continues beyond hatching. Expression profiles reveal both conservation and divergence of core myelination components between mammals and amphibians; however, direct gene-level comparisons across species require further investigation given our small sample size. The upregulation of orthologous myelin genes in the turtle PNS supports the idea that these components are conserved, although their timing, regulation, or network structure may differ across tetrapods. We based our inference of conservation on orthology and the coordinated expression of key myelin genes (e.g., ErbB2, Mag, Mpz, Mbp, Pmp22) in T. scripta. TEM analysis of turtle sciatic nerves shows myelin rings in a few axons starting at stage 21, increasing significantly by stage 24, and becoming prominent in most axons of the adult nerve. Furthermore, antibodies against MPZ, DRP2, and Kv1.1 indicate that T. scripta adult peripheral nerves at various axial levels contain myelin segments with structures consistent with appositions and Schmidt-Lanterman incisures. Overall, this is the first study of PNS myelin development in a reptile, demonstrating that myelination is a highly conserved process in vertebrates.
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Project description:We used single nucleus RNA sequencing (10x genomics) to characterize a novel 3D spheroid model - Myelin Spheres (MyS). Neuron Monoculture Spheroids (NMS) as controls. MyS comprises of neuronal progenitor cells (NPCs) with oligodendrocyte progenitor cells (OPCs) while NMS were made of only NPCs. Both NPCs and OPCs were derived from human induced pluripotent stem cells (hiPSCs) with or without an inducible SOX10 casette integrated in the genome. We performed sequencing on MyS and NMS at week 8 and 15 respectively, to understand the temporal change in oligodendrocyte maturation.
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Project description:Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1+/GFP labeled microglia isolated from the brainstem of 6-week-old mice to compare the transcriptomes of FACS-sorted versus laser capture microdissection (LCM). While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, M-bM-^HM-<50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis, increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury. Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations. Wildtype and GFP expressing microglia from mouse brainstems were flow sorted or captured by laser microdissection. Differences between the two isolation methods were verified and further examined in neurodegenerative disease models.
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