The specific galactolipids found in PNS myelin are largely the same as CNS myelin, although some glycolipids such as sulphated glucoronyl paragloboside and its derivatives are specific for PNS myelin. The major CNS myelin proteins are also found in PNS myelin, and the main ones that are special to PNS myelin are peripheral myelin protein zero (P0), peripheral myelin protein 22 (PMP22), peripheral nerve P2 protein, and periaxin.
P0 is a glycoprotein and a member of the IgCAM superfamily. It constitutes more than 50 per cent of PNS myelin and is highly specific to myelinating Schwann cells, unlike many of the other myelin proteins that are also expressed by oligodendrocytes and nonmyelinating Schwann cells. P0 is the major adhesive and structural element that mediates adhesion of the myelin lamellae, through homotypic interaction between apposing extracellular faces to form the intraperiod line. As such, it serves the same function as PLP in CNS myelin. P0 knockout mice exhibit severe hypomyelination and axon degeneration; initiation of myelination in these mice is normal, but P0 is essential for subsequent differentiation and the spiralling, compaction and maintenance of myelin, and axonal integrity. Mutations in the P0 gene, together with PMP22 and Cx32, are responsible for Charcot-Marie-Tooth neuropathies. Genetic manipulation of these genes has led to the development of animal models of peripheral neuropathies.
P2 is a basic protein and a member of the fatty acid binding protein family, with a high affinity for oleic acid, retinoic acid and retinol. It is expressed on the cytoplasmic side of compacted myelin and may be involved in intracellular fatty acid transport. P2 induces experimental allergic neuritis in animals, used as a model for the PNS demyelinating disease Guillain-Barré syndrome.
PMP22 is a tetraspan membrane glycoprotein that plays an important role in myelin synthesis and assembly. Point mutations in the PMP22 gene, such as those in the trembler mouse, result in PNS-specific dysmyelination, with phenotypes comparable to P0 knockout mice. However, development of PMP22 knockout mice showed that total disruption of the PMP22 gene results in hypermyelination and demyelination, indicating that PMP22 regulates the initiation of myelination, myelin sheath thickness, and the stability of myelin. In addition, studies in PMP22 knockout mice indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of Schwann cells with the basal lamina.
MBP is present but it may not play a major role in myelin compaction, and its function may be interchangeable with P0. In shiverer mice, the loss of MBP results in severe hypomyelination in the CNS, but PNS myelin appears normal.
PLP/DM20 is found in Schwann cells and PNS myelin, but its function is unclear. PNS myelin appears normal in PLP knockout mice and most mutations.
MAG is located in the periaxonal Schwann cell membrane, the internal and external mesaxons, the paranodal loops, and the Schmidt-Lanterman incisures. MAG has the same function in PNS and CNS myelin, participating in axonal recognition, adhesion and maintenance of myelin integrity.
Cx32 is found mainly in the paranodal regions and Schmidt-Lanterman incisures. Cx32 is supposed to form gap junctions within the myelin sheath, as well as between Schwann cells, and to be important for ion homeostasis. In addition, Cx32 gap junctions link the partially compacted second layer of myelin to the noncompact outer tongue. The presence of mutations in the X-linked Cx32 gene in Charcot-Marie-Tooth disease type X indicates a role for Cx32 in formation and maintenance of PNS myelin. Cx32 knockout mice have a similar phenotype and develop late-onset demyelination.
Periaxin is a PNS-specific glycoprotein representing about five per cent of total myelin protein. There are two isoforms, S- and L-periaxin. L-periaxin is a constituent of the DRP2 complex linking the Schwann cell cytoskeleton to the basal lamina. The expression of periaxin is developmentally regulated, being first concentrated in the adaxonal membrane as Schwann cells first ensheath axons, but becoming predominately localized to the abaxonal Schwann cell membrane apposing the basal lamina as myelin sheaths mature. The shift in localization suggests that periaxin participates in membrane-protein interactions that are required to stabilize the mature myelin sheath. Mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy and severe demyelinating Charcot-Marie-Tooth disease. Periaxin knockout mice myelinate normally, but develop a demyelinating peripheral neuropathy.
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