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 proteolipid protein gene and two leukodystrophies, Pelizaeus-Merzbacher disease 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 central nervous system confers a relatively mild phenotype while missense mutations in and duplications of this gene give rise to mild or severe forms of disease. Previously, we have interpreted the disease process in terms of the accumulation of the mutant proteins in the secretory pathway and, herein, we review the evidence in favor of such a cellular mechanism. Furthermore, on the basis of recent data we suggest that the unfolded protein response may be involved in the pathogenesis of Pelizaeus-Merzbacher disease and spastic paraplegia through a kinase signaling cascade that links the accumulation of mutant proteins in the endoplasmic reticulum of oligodendrocytes with changes in gene regulation, protein synthesis, and possibly apoptosis.