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Absence of Plekhg5 Results in Myelin Infoldings Corresponding to an Impaired Schwann Cell Autophagy, and a Reduced T-Cell Infiltration Into Peripheral Nerves

ABSTRACT: Inflammation and dysregulation of the immune system are hallmarks of several neurodegenerative diseases. An activated immune response is considered to be the cause of myelin breakdown in demyelinating disorders. In the peripheral nervous system (PNS), myelin can be degraded in an autophagy-dependent manner directly by Schwann cells or by macrophages, which are modulated by T-lymphocytes. Here, we show that the NF-κB activator Pleckstrin homology containing family member 5 (Plekhg5) is involved in the regulation of both Schwann cell autophagy and recruitment of T-lymphocytes in peripheral nerves during motoneuron disease. Plekhg5-deficient mice show defective axon/Schwann cell units characterized by myelin infoldings in peripheral nerves. Even at late stages, Plekhg5-deficient mice do not show any signs of demyelination and inflammation. Using RNAseq, we identified a transcriptional signature for an impaired immune response in sciatic nerves, which manifested in a reduced number of CD4+ and CD8+ T-cells. These findings identify Plekhg5 as a promising target to impede myelin breakdown in demyelinating PNS disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE127319 | GEO | 2020/07/27

REPOSITORIES: GEO

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Functions of HDAC1 and HDAC2 in Schwann cells during postnatal

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2011-02-25 | E-GEOD-27451 | biostudies-arrayexpress

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Functions of HDAC1 and HDAC2 in Schwann cells during postnatal

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2023-12-12 | GSE244328 | GEO

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Project description:Peripheral nerves contain axons and their enwrapping glia cells named Schwann cells (SC) that are either myelinating or non-myelinating (nmSC). Our understanding of other cells in the peripheral nervous system (PNS) remains limited. Here, we provide an unbiased single-cell transcriptomic characterization of the non-diseased rodent PNS. We identified and independently confirmed novel markers of previously underappreciated nmSC and nerve-associated fibroblasts. We also found and characterized two distinct populations of nerve-resident homeostatic myeloid cells that transcriptionally differed from central nervous system microglia. In a model of chronic autoimmune neuritis, homeostatic myeloid cells were outnumbered by infiltrating lymphocytes which modulated the local cell-cell interactome and induced a specific transcriptional response in glia cells. This response was partially shared between the peripheral and central nervous system glia identifying common immunological features across different parts of the nervous system. Our study thus identifies novel subtypes and cell-type markers of PNS cells and a partially conserved autoimmunity module induced in glia cells.

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Specific functions for ERK/MAPK signaling during PNS development

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Project description:Using the sciatic nerve as a model, we biochemically purified peripheral nervous system (PNS) myelin and systematically assessed its proteome by dedicated, partly ion mobility-enhanced data-independent acquisition (DIA) workflows with alternating low and elevated energy (MSE) modes. Specifically, we used MSE for correct quantification of highest-abundance proteins, UDMSE for deep quantitative proteome coverage, and dynamic range enhancement (DRE)-UDMSE for comparative analysis, the latter mode providing a good compromise between dynamic range, identification rate and instrument run time for routine differential myelin proteome profiling. We found that integration of the proteome data with the total nerve transcriptome is suited to determine comprehensive molecular profiles in healthy nerves and in myelin-related disorders. This work provides the most comprehensive proteome resource thus far to approach development, function and pathology of peripheral myelin, and a straightforward, accurate and sensitive workflow to address myelin diversity in health and disease.

2020-02-20 | PXD015960 | Pride

A Histone Deacetylase 3-Dependent Pathway Delimits Peripheral Myelin Growth and Functional Regeneration [ChIP-Seq]

Project description:Schwann cell remyelination defects impair functional restoration after nerve damage, contributing to peripheral neuropathies. The mechanisms that mediate remyelination block remain elusive. Upon small-molecule epigenetic screening, we identified HDAC3, a histone-modifying enzyme, as a potent inhibitor of peripheral myelinogenesis. Inhibition of HDAC3 markedly enhances myelin growth and regeneration, and improves functional recovery after peripheral nerve injury. HDAC3 antagonizes myelinogenic neuregulin/PI3K/AKT signaling axis. Moreover, genome-wide profiling analyses reveal that HDAC3 represses pro-myelinating programs through epigenetic silencing, while coordinating with p300 histone acetyltransferase to activate myelination-inhibitory programs that include HIPPO signaling effector TEAD4 to inhibit myelin growth. Schwann-cell-specific deletion of either Hdac3 or Tead4 results in a profound increase in myelin thickness in sciatic nerves. Thus, our findings identify the HDAC3-TEAD4 network as a dual-function switch of cell-intrinsic inhibitory machinery that counters myelinogenic signals and maintains peripheral myelin homeostasis, highlighting the therapeutic potential of transient HDAC3 inhibition for improving peripheral myelin repair.

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