PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus‐Merzbacher disease

Abstract

Duplication of PLP1, an X-linked gene encoding the major myelin membrane protein of the human CNS, is the most frequent cause of Pelizaeus-Merzbacher disease (PMD). Transgenic mice with extra copies of the wild type Plp1 gene, a valid model of PMD, also develop a dysmyelinating phenotype dependant on gene dosage. In this study we have examined the effect of increasing Plp1 gene dosage on levels of PLP/DM20 and on other representative myelin proteins. In cultured oligodendrocytes and early myelinating oligodendrocytes in vivo, increased gene dosage leads to elevated levels of PLP/DM20 in the cell body. During myelination, small increases in Plp1 gene dosage (mice hemizygous for the transgene) elevate the level of PLP/DM20 in oligodendrocyte soma but cause only minimal and transient effects on the protein composition and structure of myelin suggesting that cells can regulate the incorporation of proteins into myelin. However, larger increases in dosage (mice homozygous for the transgene) are not well tolerated, leading to hypomyelination and alteration in the cellular distribution of PLP/DM20. A disproportionate amount of PLP/DM20 is retained in the cell soma, probably in autophagic vacuoles and lysosomes whereas the level in myelin is reduced. Increased Plp1 gene dosage affects other myelin proteins, particularly MBP, which is transitorily reduced in hemizygous mice but consistently and markedly lower in homozygotes in both myelin and naïve or early myelinating oligodendrocytes. Whether the reduced MBP is implicated in the pathogenesis of dysmyelination is yet to be established.

Stereological Evidence for De/Re-Generation of Myelin Sheaths in Aged Brain White Matter of Female Rats

“…In previous studies on aged monkey brains, two of the age-related alterations seen in this study in myelin sheaths (local splitting of the major dense lines and the formation of myelin balloons) were observed in the anterior commissure, primary visual cortex and corpus callosum (Peters et al, 2000;Peters and Sethares, 2002;Sandell and Peters, 2003). Moreover, it has been reported that myelin sheath changes were also involved in various diseases (Lassmann et al, 1997;Myers, 1998;Biffiger et al, 2000), and in various experimental conditions (Blakemore, 1978;Chang, 1990;Anderson et al, 1998;Franco-Pons et al, 2007;Karim et al, 2007;Skripuletz et al, 2008;). Similar age-related changes in the myelin sheaths of elderly rats were observed in this study (Fig.4A, Fig.4B).…”

Distinct endocytic recycling of myelin proteins promotes oligodendroglial membrane remodeling

“…Overexpression of high levels of PLP results in sequestration of cholesterol to endocytic compartments and reduced incorporation of MBP in myelin, probably contributing to the dysmyelinating pathology observed in the case of PLP gene duplication in vivo (Karim et al, 2007;Simons et al, 2002). In Oli-neu cells, the level of transiently expressed PLP is not sufficient to induce cholesterol sequestration in endocytic compartments (Kramer-Albers et al, 2006).…”

Modeling the Mutational and Phenotypic Landscapes of Pelizaeus-Merzbacher Disease with Human iPSC-Derived Oligodendrocytes

“…In prior literature, five possible molecular defects have been ascribed to certain PLP1 mutations: reduced expression, overexpression, 38 direct disruption of protein functional domains, 26 protein mistrafficking, 25,39,40 and protein misfolding leading to endoplasmic reticulum (ER) stress. 38,[41][42][43] The occurrence of these defects individually or in combination most likely accounts for much of the clinical heterogeneity observed in PMD. However, because prior studies have largely focused on mutations one at a time, it is difficult to ascribe any findings to a mutation apart from that in which it was originally observed.…”