Evolution of a neuroprotective function of central nervous system myelin

The 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.