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, P₀, as the major protein of myelin. To investigate possible reasons for this molecular switch, we genetically engineered mice to express P₀ instead of PLP in CNS myelin. In the absence of PLP, the ancestral P₀ provided a periodicity to mouse compact CNS myelin that was identical to mouse PNS myelin, where P₀ is the major structural protein today. The PLP–P₀ 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 P₀ and PLP in CNS myelin had a normal lifespan and no axonal degeneration. These data support the hypothesis that the P₀–PLP shift during vertebrate evolution provided a vital neuroprotective function to myelin-forming CNS glia.