The time-course of the appearance of newly synthesized lipids and proteins in myelin indicates that myelin is not laid down as a unit. Different components are synthesized and processed in different cellular compartments, are transported to the sites of myelin formation by different mechanisms, and show different rates of entry into the myelin sheath. For example, MBP enters the myelin sheath with almost no lag after synthesis, whereas proteolipid protein enters myelin with a lag-time of 30-40 min following synthesis. Once protein synthesis is stopped with cyclo-heximide, the entry of MBP is halted immediately, but proteolipid protein continues to be incorporated into myelin for 30 min. These data indicate that MBP and PLP are assembled by different mechanisms, with PLP taking a longer and more circuitous route through the cytoplasm. Lipids also continue to be incorporated into myelin for 4 h after protein synthesis has stopped.
MBP is synthesized on free polyribosomes near the plasma membrane or the adjacent myelin sheath. The myelin membrane is surrounded by and infiltrated with cytoplasmic channels, called the outer loops and longitudinal incisures of Schmidt-Lantermann, respectively. Myelin basic protein mRNA is translocated from the nucleus to the myelin membrane via these cytoplasmic channels. MBP synthesized here is rapidly sequestered into the myelin sheath and appears in the cytoplasmic leaflet of compact myelin (major dense lines). mRNAs for several other myelin proteins follow similar trafficking pathways.
Proteolipid protein and DM 20 are synthesized on polyribosomes bound to the endoplasmic reticulum. The nascent protein is inserted into the endoplasmic reticulum and passes through the Golgi apparatus to the plasma membrane and myelin sheath via vesicular transport. Inclusion in the plasma membrane occurs by fusion of the vesicles with the plasma membrane. The inside of the vesicle after fusion becomes the outside of the plasma membrane. As a conse quence, substances transported to the plasma membrane via vesicles end up in the extracellular leaflet of the myelin sheath. MAG resembles proteolipid protein as far as the site of synthesis and transport to the plasma membrane are concerned.
The same two mechanisms of synthesis and transport can be distinguished for myelin lipids, i.e., the routes of PLP and MBP, respectively. The endoplasmic reticulum is the site of synthesis of phosphatidyl-choline and cholesterol. The Golgi apparatus is the site of synthesis of cerebroside, sulfatide, sphin-gomyelin, and gangliosides. The lipids are transported from the Golgi apparatus to the plasma membrane by a vesicle-mediated process. Expression on the cell surface occurs by fusion of the vesicles with the plasma membrane. The lipids are located predominantly in the extracellular leaflet of the myelin lamellae. In contrast, the myelin phospholipids that predominantly reside on the inner leaflet, including phos-phatidylserine and ethanolamine plasmalogens, are synthesized in the superficial cytoplasmic channels of the myelin sheath and rapidly enter compact myelin, possibly with phospholipid transfer proteins as carriers. Several other phospholipids are also synthesized in the superficial cytoplasmic channels.
After reaching the outermost myelin layers, substances penetrate to the deepest layers over a period of a few days. This movement of substances from outer to inner layers occurs at rates consistent with lateral diffusion along the spirally wound bilayer.
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