Evolution of a neuroprotective function of central nervous system myelin

Xinghua Yin,Wendy B Macklin,Klaus-Armin Nave,Rena C Baek,Daniel A Kirschner,Bruce D Trapp,Yasuhisa Fujii,Alan Peterson

doi:10.1083/jcb.200509174

Abstract

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.

Highlights

IntroductionTightly compacted membrane that surrounds axons in the central nervous system (CNS) and peripheral nervous system (PNS)
Myelin is a multilamellar, tightly compacted membrane that surrounds axons in the central nervous system (CNS) and peripheral nervous system (PNS)
The purpose of this study was to investigate whether the shift from P0 to proteolipid protein (PLP) during CNS myelin evolution was related to a new function of myelinating CNS glia

Summary

Introduction

Tightly compacted membrane that surrounds axons in the central nervous system (CNS) and peripheral nervous system (PNS). Myelin helps concentrate voltage-gated Na+ channels at nodes of Ranvier (Pedraza et al, 2001), the short unmyelinated regions between myelin segments. Mammalian CNS and PNS myelin serve similar functions, they can be distinguished by two major features. Oligodendrocytes form multiple myelin internodes in the CNS, whereas Schwann cells form single myelin internodes in the PNS. Myelin proteolipid protein (PLP), a four-transmembrane-domain protein, represents >50% of the protein in mammalian CNS myelin (Milner et al, 1985), whereas P0 protein, a type I integral membrane glycoprotein and member of the immunoglobulin gene super family, represents >70% of the total myelin protein in mammalian PNS myelin (Lemke and Axel, 1985)

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