Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease
Aberrant trafficking of a proteolipid protein in a mild Pelizaeus-Merzbacher disease
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DOI：
10.1016/j.neuroscience.2006.05.067
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发表时间：
2006-01-01
期刊：
影响因子：
3.3
通讯作者：
Osaka, H.
中科院分区：
文献类型：
--
作者：
Koizume, S.;Takizawa, S.;Osaka, H.
Pelizaeus-Merzbacher病(PMD)是一种罕见的X连锁脑白质营养不良，由蛋白脂蛋白1(PLP1)基因突变引起。以往的研究表明，具有疾病相关突变的蛋白脂蛋白(PLPs)在运输到细胞表面的过程中被错误折叠并滞留在内质网(ER)中，最终导致PMD中少突胶质细胞的死亡。在这里，我们报告了一个非常轻微的表型携带PLP1基因外显子4的新突变(485G->；T)的PMD患者，该突变导致蛋白质中的Trp(162)Leu替换。我们还研究了这种突变的PLP在COS-7细胞中的细胞内转运。瞬时转染的突变体PLP(W162L)与增强型绿色荧光蛋白(EGFP)或短肽标签融合后不携带到质膜上。然而，与以前的研究相反，这个突变的PLP没有保留在内质网中，这表明新翻译的蛋白质逃脱了质量控制机制。我们还发现，突变的PLP以时间依赖的方式积累在核膜(NE)中。这种突变的PLP分布在内质网外，表型非常温和，支持错误折叠突变蛋白在内质网中积累导致PMD严重表型的观点。(C)2006年IBRO。爱思唯尔有限公司出版。保留所有权利。
Pelizaeus-Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by proteolipid protein 1 (PLP1) gene mutations. Previous studies indicated that proteolipid proteins (PLPs) with disease-associated mutations are misfolded and trapped in the endoplasmic reticulum (ER) during transportation to the cell surface, which eventually leads to oligodendrocyte cell death in PMD. Here we report a PMD patient with a very mild phenotype carrying a novel mutation (485G -> T) in exon 4 of the PLP1 gene that causes a Trp(162)Leu substitution in the protein. We also investigated intracellular trafficking of this mutant PLP in COS-7 cells. Transiently transfected mutant PLp(W162L) fused to an enhanced green fluorescent protein (EGFP) or a short peptide tag was not carried to the plasma membrane. However, in contrast to previous studies, this mutant PLP was not retained in the ER, indicating an escape of the newly translated protein from the quality control machinery. We also found that the mutant PLP accumulated in the nuclear envelope (NE) in a time-dependent manner. This mutant PLP, with its distribution outside the ER and a very mild phenotype, supports the idea that accumulation of misfolded mutant protein in the ER causes the severe phenotype of PMD. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.