The axon-myelin unit in development and degenerative disease

Axons are electrically excitable, cable-like neuronal processes that relay information between neurons within the nervous system and between neurons and peripheral target tissues. In the central and peripheral nervous systems, most axons over a critical diameter are enwrapped by myelin, which reduces internodal membrane capacitance and facilitates rapid conduction of electrical impulses. The spirally wrapped myelin sheath, which is an evolutionary specialisation of vertebrates, is produced by oligodendrocytes and Schwann cells; in most mammals myelination occurs during postnatal development and after axons have established connection with their targets. Myelin covers the vast majority of the axonal surface, influencing the axon's physical shape, the localisation of molecules on its membrane and the composition of the extracellular fluid (in the periaxonal space) that immerses it. Moreover, myelinating cells play a fundamental role in axonal support, at least in part by providing metabolic substrates to the underlying axon to fuel its energy requirements. The unique architecture of the myelinated axon, which is crucial to its function as a conduit over long distances, renders it particularly susceptible to injury and confers specific survival and maintenance requirements. In this review we will describe the normal morphology, ultrastructure and function of myelinated axons, and discuss how these change following disease, injury or experimental perturbation, with a particular focus on the role the myelinating cell plays in shaping and supporting the axon

New species can broaden myelin research: suitability of little skate, Leucoraja erinacea

© The Author(s), 2021. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Moebius, W., Huemmert, S., Ruhwedel, T., Kuzirian, A., & Gould, R. New species can broaden myelin research: suitability of little skate, Leucoraja erinacea. Life, 11(2), (2021): 136, https://doi.org/10.3390/life11020136.Although myelinated nervous systems are shared among 60,000 jawed vertebrates, studies aimed at understanding myelination have focused more and more on mice and zebrafish. To obtain a broader understanding of the myelination process, we examined the little skate, Leucoraja erinacea. The reasons behind initiating studies at this time include: the desire to study a species belonging to an out group of other jawed vertebrates; using a species with embryos accessible throughout development; the availability of genome sequences; and the likelihood that mammalian antibodies recognize homologs in the chosen species. We report that the morphological features of myelination in a skate hatchling, a stage that supports complex behavioral repertoires needed for survival, are highly similar in terms of: appearances of myelinating oligodendrocytes (CNS) and Schwann cells (PNS); the way their levels of myelination conform to axon caliber; and their identity in terms of nodal and paranodal specializations. These features provide a core for further studies to determine: axon–myelinating cell communication; the structures of the proteins and lipids upon which myelinated fibers are formed; the pathways used to transport these molecules to sites of myelin assembly and maintenance; and the gene regulatory networks that control their expressions.This research received no external funding

Proteome Profile of Myelin in the Zebrafish Brain

The velocity of nerve conduction along vertebrate axons depends on their ensheathment with myelin. Myelin membranes comprise specialized proteins well characterized in mice. Much less is known about the protein composition of myelin in non-mammalian species. Here, we assess the proteome of myelin biochemically purified from the brains of adult zebrafish (Danio rerio), considering its increasing popularity as model organism for myelin biology. Combining gel-based and gel-free proteomic approaches, we identified > 1,000 proteins in purified zebrafish myelin, including all known constituents. By mass spectrometric quantification, the predominant Ig-CAM myelin protein zero (MPZ/P0), myelin basic protein (MBP), and the short-chain dehydrogenase 36K constitute 12%, 8%, and 6% of the total myelin protein, respectively. Comparison with previously established mRNA-abundance profiles shows that expression of many myelin-related transcripts coincides with the maturation of zebrafish oligodendrocytes. Zebrafish myelin comprises several proteins that are not present in mice, including 36K, CLDNK, and ZWI. However, a surprisingly large number of ortholog proteins is present in myelin of both species, indicating partial evolutionary preservation of its constituents. Yet, the relative abundance of CNS myelin proteins can differ markedly as exemplified by the complement inhibitor CD59 that constitutes 5% of the total zebrafish myelin protein but is a low-abundant myelin component in mice. Using novel transgenic reporter constructs and cryo-immuno electron microscopy, we confirm the incorporation of CD59 into myelin sheaths. These data provide the first proteome resource of zebrafish CNS myelin and demonstrate both similarities and heterogeneity of myelin composition between teleost fish and rodents

Peroxisomal dysfunctions cause lysosomal storage and axonal Kv1 channel redistribution in peripheral neuropathy

Impairment of peripheral nerve function is frequent in neurometabolic diseases, but mechanistically not well understood. Here, we report a novel disease mechanism and the finding that glial lipid metabolism is critical for axon function, independent of myelin itself. Surprisingly, nerves of Schwann cell-specific Pex5 mutant mice were unaltered regarding axon numbers, axonal calibers, and myelin sheath thickness by electron microscopy. In search for a molecular mechanism, we revealed enhanced abundance and internodal expression of axonal membrane proteins normally restricted to juxtaparanodal lipid-rafts. Gangliosides were altered and enriched within an expanded lysosomal compartment of paranodal loops. We revealed the same pathological features in a mouse model of human Adrenomyeloneuropathy, preceding disease-onset by one year. Thus, peroxisomal dysfunction causes secondary failure of local lysosomes, thereby impairing the turnover of gangliosides in myelin. This reveals a new aspect of axon-glia interactions, with Schwann cell lipid metabolism regulating the anchorage of juxtaparanodal Kv1-channels

The Axon-Myelin Unit in Development and Degenerative Disease

Axons are electrically excitable, cable-like neuronal processes that relay information between neurons within the nervous system and between neurons and peripheral target tissues. In the central and peripheral nervous systems, most axons over a critical diameter are enwrapped by myelin, which reduces internodal membrane capacitance and facilitates rapid conduction of electrical impulses. The spirally wrapped myelin sheath, which is an evolutionary specialisation of vertebrates, is produced by oligodendrocytes and Schwann cells; in most mammals myelination occurs during postnatal development and after axons have established connection with their targets. Myelin covers the vast majority of the axonal surface, influencing the axon's physical shape, the localisation of molecules on its membrane and the composition of the extracellular fluid (in the periaxonal space) that immerses it. Moreover, myelinating cells play a fundamental role in axonal support, at least in part by providing metabolic substrates to the underlying axon to fuel its energy requirements. The unique architecture of the myelinated axon, which is crucial to its function as a conduit over long distances, renders it particularly susceptible to injury and confers specific survival and maintenance requirements. In this review we will describe the normal morphology, ultrastructure and function of myelinated axons, and discuss how these change following disease, injury or experimental perturbation, with a particular focus on the role the myelinating cell plays in shaping and supporting the axon

Rio-Hortega's drawings revisited with fluorescent proteins define a cytoplasm filled channel system of CNS myelin

A century ago this year, Pío del Río-Hortega (1921) coined the term ‘oligodendroglia’ for the ‘interfascicular glia’ with very few processes, launching an extensive discovery effort on his new cell type. One hundred years later, we review his original contributions to our understanding of the system of cytoplasmic channels within myelin in the context of what we observe today using light and electron microscopy of genetically encoded fluorescent reporters and immunostaining. We use the term myelinic channel system to describe the cytoplasm-delimited spaces associated with myelin; being the paranodal loops, inner and outer tongues, cytoplasm-filled spaces through compact myelin and further complex motifs associated to the sheath. Using a central nervous system myelinating cell culture model that contains all major neural cell types and produces compact myelin, we find that td-tomato fluorescent protein delineates the myelinic channel system in a manner reminiscent of the drawings of adult white matter by Río-Hortega, despite that he questioned whether some cytoplasmic figures he observed represented artefact. Together, these data lead us to propose a slightly revised model of the ‘unrolled’ sheath. Further, we show that the myelinic channel system, while relatively stable, can undergo subtle dynamic shape changes over days. Importantly, we capture an under-appreciated complexity of the myelinic channel system in mature myelin sheaths

BACE1 Processing of NRG1 Type III Produces a Myelin-Inducing Signal but Is Not Essential for the Stimulation of Myelination

Myelin sheath thickness is precisely adjusted to axon caliber, and in the peripheral nervous system, neuregulin 1 (NRG1) type III is a key regulator of this process. It has been proposed that the protease BACE1 activates NRG1 dependent myelination. Here, we characterize the predicted product of BACE1-mediated NRG1 type III processing in transgenic mice. Neuronal overexpression of a NRG1 type III-variant, designed to mimic prior cleavage in the juxtamembrane stalk region, induces hypermyelination in vivo and is sufficient to restore myelination of NRG1 type III-deficient neurons. This observation implies that the NRG1 cytoplasmic domain is dispensable and that processed NRG1 type III is sufficient for all steps of myelination. Surprisingly, transgenic neuronal overexpression of full-length NRG1 type III promotes hypermyelination also in BACE1 null mutant mice. Moreover, NRG1 processing is impaired but not abolished in BACE1 null mutants. Thus, BACE1 is not essential for the activation of NRG1 type III to promote myelination. Taken together, these findings suggest that multiple neuronal proteases collectively regulate NRG1 processing. © 2011 Wiley Periodicals, Inc

Myelination generates aberrant ultrastructure that is resolved by microglia

To enable rapid propagation of action potentials, axons are ensheathed by myelin, a multilayered insulating membrane formed by oligodendrocytes. Most of the myelin is generated early in development, resulting in the generation of long-lasting stable membrane structures. Here, we explored structural and dynamic changes in central nervous system myelin during development. To achieve this, we performed an ultrastructural analysis of mouse optic nerves by serial block face scanning electron microscopy (SBF-SEM) and confocal time-lapse imaging in the zebrafish spinal cord. We found that myelin undergoes extensive ultrastructural changes during early postnatal development. Myelin degeneration profiles were engulfed and phagocytosed by microglia using exposed phosphatidylserine as one “eat me” signal. In contrast, retractions of entire myelin sheaths occurred independently of microglia and involved uptake of myelin by the oligodendrocyte itself. Our findings show that the generation of myelin early in development is an inaccurate process associated with aberrant ultrastructural features that require substantial refinement.</p

Decoupling astrocytes in adult mice impairs synaptic plasticity and spatial learning

The mechanisms by which astrocytes modulate neural homeostasis, synaptic plasticity, and memory are still poorly explored. Astrocytes form large intercellular networks by gap junction coupling, mainly composed of two gap junction channel proteins, connexin 30 (Cx30) and connexin 43 (Cx43). To circumvent developmental perturbations and to test whether astrocytic gap junction coupling is required for hippocampal neural circuit function and behavior, we generate and study inducible, astrocyte-specific Cx30 and Cx43 double knockouts. Surprisingly, disrupting astrocytic coupling in adult mice results in broad activation of astrocytes and microglia, without obvious signs of pathology. We show that hippocampal CA1 neuron excitability, excitatory synaptic transmission, and long-term potentiation are significantly affected. Moreover, behavioral inspection reveals deficits in sensorimotor performance and a complete lack of spatial learning and memory. Together, our findings establish that astrocytic connexins and an intact astroglial network in the adult brain are vital for neural homeostasis, plasticity, and spatial cognition