Pelizaeus–Merzbacher disease: pathogenic mechanisms and insights into the roles of proteolipid protein 1 in the nervous system

Abstract

After over 50 years of study, a clear understanding of the biological roles of proteolipid protein 1 (PLP1) is lacking [1]. The PLP1 gene encodes two major products, PLP1 itself, and DM20, encoded by an alternatively spliced transcript, that lacks 35 residues from the cytoplasmic domain of PLP1. PLP1 comprises about half the protein mass of central nervous system myelin. PLP1 is also present in the peripheral nervous system, however it constitutes only a small fraction of myelin protein. PLP1 is a highly hydrophobic transmembrane protein. In addition to a high content of hydrophobic amino acids, PLP1 is anchored to the lipid bilayer by fatty acylation of several cysteine residues. DM20 is present at about 10% of the level of PLP1 in the CNS while in the PNS it is present at approximately equivalent amounts [2]. Because of its abundance in CNS myelin, PLP1 has generally been thought of as an important structural protein. Mutations of the PLP1 gene cause a broad range of clinical phenotypes that affect the central nervous system and, in some instances, the peripheral nervous system as well [3,4]. Analysis of the consequences of these mutations offers glimpses into the functions of PLP1, the most abundant protein in CNS myelin, as well as into the cellular effects of abnormalities in PLP1. Null mutations are the most informative for inferring the normal biological functions of a gene product. Belying its abundance in normal CNS myelin, complete lack of PLP1 and DM20 results in a surprisingly mild phenotype in both mice and in humans. Griffiths et al. [5] found that Plp1 knockout mice behave normally until about 15 months of age, when they develop progressive extremity weakness. Early myelination