Evolution of a neuroprotective function of central nervous system myelin

he central nervous system (CNS) of terrestrial vertebrates underwent a prominent molecular change when a tetraspan membrane protein, myelin proteolipid protein (PLP), replaced the type I integral membrane protein, P-0, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P-0 instead of PLP in CNS myelin. In the absence of PLP, the ancestral P-0 provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P-0 is the major structural protein today. The PLP-P-0 shift resulted in reduced myelin internode length, degeneration of myelinated axons, severe neurological disability, and a 50% reduction in lifespan. Mice with equal amounts of P-0 and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P-0-PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia