Proteolipid protein cannot replace P0 protein as the major structural protein of peripheral nervous system myelin.

The central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when proteolipid protein (PLP) replaced P-0 protein as the most abundant protein of CNS myelin. However, PLP did not replace P-0 in peripheral nervous system (PNS) myelin. To investigate the possible consequences of a PLP to P-0 shift in PNS myelin, we engineered mice to express PLP instead of P-0 in PNS myelin (PLP-PNS mice). PLP-PNS mice had severe neurological disabilities and died between 3 and 6 months of age. Schwann cells in sciatic nerves from PLP-PNS mice sorted axons into one-to-one relationships but failed to form myelin internodes. Mice with equal amounts of P-0 and PLP had normal PNS myelination and lifespans similar to wild-type (WT) mice. When PLP was overexpressed with one copy of the P-0 gene, sciatic nerves were hypomyelinated; mice displayed motor deficits, but had normal lifespans. These data support the hypothesis that while PLP can co-exist with P-0 in PNS myelin, PLP cannot replace P-0 as the major structural protein of PNS myelin. GLIA 2015;63:66-77 Main Points We engineered mice to express PLP instead of P0 in PNS myelin (PLP-PNS mice), and these mice had severe neurological disabilities and died between 3 and 6 months of age. Schwann cells in sciatic nerves from PLP-PNS mice sorted axons into one-to-one relationships but failed to form myelin internodes. When PLP was overexpressed with one copy of the P0 gene, sciatic nerves were hypomyelinated, and mice displayed motor deficits but had normal lifespans.