Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene

A decade after the genetic link was established between mutations in the pr oteolipid protein gene and two leukodystropkies, Pelizaeus-Merzbacher disea se and spastic paraplegia, the molecular mechanisms underlying pathogenesis are beginning to come to light. Data from animal models of these diseases suggest that the absence of proteolipid protein gene products in the centra l nervous system confers a relatively mild phenotype while missense mutatio ns in and duplications of this gene give rise to mild or severe forms of di sease. Previously, we have interpreted the disease process in terms of the accumulation of the mutant proteins in the secretory pathway and, herein, w e review the evidence in favor of such a cellular mechanism. Furthermore, o n the basis of recent data we suggest that the unfolded protein response ma y be involved in the pathogenesis of Pelizaeus-Merzbacher disease and spast ic paraplegia through a kinase signaling cascade that links the accumulatio n of mutant proteins in the endoplasmic reticulum of oligadendrocytes with changes in gene regulation, protein synthesis, and possibly apoptosis. (C) 2001 Wiley-Liss, Inc.