While the former is well understood thanks to many studies on the role of myelin basic protein (Mbp) in myelin assembly (at cellular, biochemical and biophysical levels reviewed by Aggarwal, Yurlova, & Simons, 2011 Bakhti et al., 2014), the compaction of myelin extracellular sides remains elusive. Myelin compaction of the already formed myelin layers can be dissociated in two phases: intracellular and extracellular leaflet compaction.
For example, functional myelination still occurs in specific brain areas in the absence of Fyn, a kinase of the SLK family with pivotal roles in transducing and integrating axon-derived signals (reviewed by Kramer-Albers & White, 2011 White & Kramer-Albers, 2014). Knocking-out important structural or regulatory players often have less-than-expected effects. The complex process of myelination is a robust one, with many regulatory “checkpoints” and redundant systems to safeguard the final product: a healthy and properly myelinated axon. Myelin maturation requires the exclusion of water-rich media from large compact myelin domains (Bakhti, Aggarwal, & Simons, 2014), which results in intimate membrane appositions recognized by electron microscopy as the major dense line (MDL, condensation of the intracellular space) and intra-period line (IPL, condensation of the extracellular space). Signaling continues through the process of growth and maturation of myelin (reviewed by Baron & Hoekstra, 2010 Jacob, Lebrun-Julien, & Suter, 2011 Pereira, Lebrun-Julien, & Suter, 2012 Quarles, Macklin, & Morell, 2006 Simons & Trotter, 2007 Snaidero & Simons, 2017 White & Kramer-Albers, 2014). Complex glia-axon communication initiates the first contact with axons and induces glial cell polarity, followed by the construction of a few turns of incipient myelin. Myelinating glial cells have the important task of building and maintaining large expansions of their membranes that enwrap axons and provide the basis for saltatory nerve impulse propagation, thus conditioning the function of neural circuits.
By ensuring lysosomal functional integrity and adequate subcellular location of effector and regulatory proteins, ApoD guarantees the glycolipid recycling and glycocalyx removal required to complete myelin compaction. Exogenous ApoD rescues ApoD-KO hypersialylated glycocalyx in astrocytes, demonstrating that ApoD is necessary and sufficient to control glycocalyx composition in glial cells. In the absence of ApoD, partial permeabilization of lysosomes alters Neu1 location as well. ApoD-KO myelin becomes depleted of Neu3 and enriched in Fyn, a kinase with pivotal roles in transducing axon-derived signals into myelin properties. In peripheral nervous system, Neu3 membrane sialidase and lysosomal Neu1 are coordinately expressed with ApoD in subsets of Schwann cells. Without ApoD, the sialylated glycocalyx is maintained and ganglioside content remains high. Late in myelin maturation period, ApoD affects lipogenic and growth-related, but not stress-responsive, signaling pathways. Lack of ApoD specifically modifies Plp and P0 protein expression, but not Mbp or Mag. Myelination initiation, growth, intracellular leaflet compaction, myelin thickness or internodal length remain unaltered. What is required to initiate this membrane-zipping process? Knocking-out the Lipocalin Apolipoprotein D (ApoD), essential for lysosomal functional integrity in glial cells, results in a specific defect in myelin extracellular leaflet compaction in peripheral and central nervous system, which results in reduced conduction velocity and suboptimal behavioral outputs: motor learning is compromised. Removal of the negatively charged glycocalyx becomes the limiting factor in such transition. To compact the extracellular sides of myelin, an important transition must take place: from membrane sliding, while building the wraps, to membrane adhesion and water exclusion.
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