PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease
PLP overexpression perturbs myelin protein composition and myelination in a mouse model of Pelizaeus-Merzbacher disease
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DOI：
10.1002/glia.20465
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发表时间：
2007-03-01
期刊：
影响因子：
6.2
通讯作者：
Mclaughlin, Mark
中科院分区：
文献类型：
--
作者：
Karim, Saadia A.;Barrie, Jennifer A.;Mclaughlin, Mark
PLP1 是编码人类中枢神经系统主要髓磷脂膜蛋白的 X 连锁基因，其重复是导致佩利扎乌斯-梅茨巴赫病 (PMD) 的最常见原因。具有额外野生型 Plp1 基因拷贝的转基因小鼠（PMD 的有效模型）也会出现依赖于基因剂量的髓鞘形成障碍表型。在这项研究中，我们研究了增加 Plp1 基因剂量对 PLP/DM20 和其他代表性髓磷脂蛋白水平的影响。在体内培养的少突胶质细胞和早期髓鞘化少突胶质细胞中，基因剂量增加导致细胞体内PLP/DM20水平升高。在髓鞘形成过程中，Plp1 基因剂量的小幅增加（转基因半合子小鼠）会提高少突胶质细胞体中 PLP/DM20 的水平，但对髓磷脂的蛋白质组成和结构仅造成最小且短暂的影响，表明细胞可以调节蛋白质掺入髓磷脂。然而，剂量的大幅增加（转基因纯合小鼠）的耐受性不佳，导致髓鞘形成不足和 PLP/DM20 细胞分布的改变。不成比例的 PLP/DM20 量保留在细胞体中，可能保留在自噬液泡和溶酶体中，而髓磷脂中的水平降低。 Plp1基因剂量的增加会影响其他髓磷脂蛋白，特别是MBP，其在半合子小鼠中暂时减少，但在髓磷脂和幼稚或早期髓鞘少突胶质细胞的纯合子中持续且显着降低。 MBP 降低是否与髓鞘形成障碍的发病机制有关尚待确定。 (c) 2006 Wiley-Liss, Inc.
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 naive or early myelinating oligodendrocytes. Whether the reduced MBP is implicated in the pathogenesis of dysmyelination is yet to be established. (c) 2006 Wiley-Liss, Inc.