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

Abstract

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.

Maturation-dependent sensitivity of oligodendrocyte lineage cells to apoptosis: implications for normal development and disease

“…Different PLP mutations can result in either severe or mild forms of PMD. 117 Severe PMD is characterized by extensive apoptosis of mature OLs and very little compacted myelin. In contrast, there is less OL apoptosis in mild PMD although the cells are inefficient at properly synthesizing normal myelin sheaths.…”

Differences in endoplasmic-reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein

“…The underlying pathogenic mechanism of missense mutations in PLP is suggested to be the accumulation of the mutant protein in the ER, which leads to activation of the UPR and oligodendrocyte apoptosis (Gow and Lazzarini, 1996;Gow et al, 1998;Southwood and Gow, 2001;Southwood et al, 2002). The extent of PLP accumulation in the ER is likely to be controlled, at least in part, by the rate at which the polypeptide is degraded.…”

“…However, the disease caused by missense mutations can range in phenotypic severity from mild PMD and late-onset spastic paraplegia type 2 (SPG2), which is characterised by hypomyelination and thinning of the myelin sheath (Hodes et al, 1997;Kobayashi et al, 1994), to severe connatal PMD associated with widespread oligodendrocyte apoptosis and a virtual absence of compact myelin Hudson et al, 1989). The critical factors that determine whether a particular mutation of the gene encoding PLP gives rise to a mild disease with hypomyelination or a severe disease with oligodendrocyte apoptosis are currently poorly understood (Dhaunchak and Nave, 2007;Gow and Lazzarini, 1996;Gow et al, 1998;Kramer-Albers et al, 2006;Southwood and Gow, 2001).…”

His36Pro point‐mutated proteolipid protein retained in the endoplasmic reticulum of oligodendrocytes in the Shaking pup

“…Studies have shown that the absence of PLP/ DM20 in Plp gene knock-out mice (Boison and Stoffel, 1994;Klugmann et al, 1997), while not preventing most axons from being myelinated, disrupts normal assembly of the myelin sheath with apposition of the extracytoplasmic surfaces and absence of the intraperiod line. Missense mutations in the conservative amino acid regions in this gene can, however, cause severe forms of disease which feature oligodendrocyte apoptosis and absence of compact myelin (Knapp et al, 1986;Ghandour and Skoff, 1988;Verity et al, 1990;Lipsitz et al, 1998;Gow et al, 1998;Southwood and Gow, 2001). These findings demonstrate a more significant impact of the mutated proteolipid proteins on myelination than the lack of the normal proteins.…”