MANY NATURALLY-OCCURRING MUTATIONS OF MYELIN PROTEOLIPID PROTEIN IMPAIR ITS INTRACELLULAR-TRANSPORT
MANY NATURALLY-OCCURRING MUTATIONS OF MYELIN PROTEOLIPID PROTEIN IMPAIR ITS INTRACELLULAR-TRANSPORT
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DOI：
10.1002/jnr.490370504
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发表时间：
1994-04-01
影响因子：
4.2
通讯作者：
LAZZARINI, RA
中科院分区：
文献类型：
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作者：
GOW, A;FRIEDRICH, VL;LAZZARINI, RA
来自哺乳动物中枢神经系统（CNS）髓磷脂的蛋白脂质蛋白（PLP）的一级结构高度保守，在小鼠、大鼠、狗、牛和人蛋白质之间仅有三个氨基酸差异。此外，在特定物种内，尚未鉴定出蛋白质的多态性。最近的兴趣集中在少突胶质细胞中PLP的靶向以及这种蛋白质的突变形式在产生髓鞘形成障碍或髓鞘形成不足疾病中所起的作用。我们以前表达的人cDNA编码PLP在瞬时转染的Cos-7细胞和其特征在于在这个简单的异源系统中的蛋白质的亚细胞分布。在当前的研究中，我们使用相同的范式来检查PLP基因中的五个错义突变对编码蛋白质加工的影响。选择的突变跨越PLP的羧基末端的一半，并涵盖其中大多数突变已被鉴定的蛋白质的那部分。我们的研究结果表明，运输的所有突变检查被逮捕的分泌途径在早期阶段，导致突变蛋白质积累在内质网。因此，蛋白质错误折叠和PLP未能到达少突胶质细胞的细胞表面的共同机制，而不是突变蛋白在细胞表面不能执行某些关键功能，可能是由许多PLP突变引起的疾病的原因。我们的研究结果，与其他人一起，促使我们推测，在PLP突变体中观察到的病理生物学可能是由于内质网中错误折叠蛋白的积累引起的少突胶质细胞死亡。这种推测与以下观察结果一致：携带错误折叠的PLP的少突胶质细胞（如jimpy突变体）增殖但迅速死亡，而来自PLP缺失的少突胶质细胞存活并产生缺乏PLP的髓鞘样膜。(C)1994 Wiley-Liss，Inc.
The primary structure of the proteolipid protein (PLP) from the central nervous system (CNS) myelin of mammals is highly conserved with only three amino acid differences between the mouse, rat, dog, bovine, and human proteins. Furthermore, within a particular species no polymorphisms in the protein have been identified. Recent interest has focused on the targeting of PLP in oligodendrocytes and the role that mutant forms of this protein play in generating dysmyelinating or hypomyelinating diseases. We previously expressed the human cDNA encoding PLP in transiently transfected Cos-7 cells and characterized the subcellular distribution of the protein in this simple heterologous system. In the current study we have used the same paradigm to examine the effect of five missense mutations in the PLP gene on processing of the encoded protein. The mutations chosen span the carboxy-terminal half of PLP and encompass that part of the protein in which most mutations have been identified. Our results show that transport of all mutations examined was arrested in the secretory pathway at an early stage, causing the mutant proteins to accumulate in the endoplasmic reticulum. Thus, a common mechanism of protein misfolding and failure of PLP to reach the cell surface of oligodendrocytes rather than the inability of the mutant protein to perform some crucial function at the cell surface may be responsible for the diseases caused by many PLP mutations. Our results, together with those of others, prompt us to speculate that the pathobiology observed in PLP mutants may result from oligodendrocyte cell death caused by the accumulation of misfolded protein in the endoplasmic reticulum. This speculation is consistent with the observations that oligodendrocytes bearing misfolded PLP, as in the jimpy mutant, proliferate but die rapidly while oligodendrocytes from PLP deletion survive and produce a myelin-like membrane which lacks PLP. (C) 1994 Wiley-Liss, Inc.