Gow A, Friedrich V L, Lazzarini R A
Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, New York 10029-6574.
J Neurosci Res. 1994 Apr 1;37(5):574-83. doi: 10.1002/jnr.490370504.
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.
哺乳动物中枢神经系统（CNS）髓磷脂中的蛋白脂蛋白（PLP）一级结构高度保守，小鼠、大鼠、狗、牛和人类的蛋白质之间只有三个氨基酸差异。此外，在特定物种内尚未发现该蛋白存在多态性。最近的研究兴趣集中在PLP在少突胶质细胞中的靶向作用以及该蛋白的突变形式在引发脱髓鞘或髓鞘形成不足疾病中所起的作用。我们之前在瞬时转染的Cos-7细胞中表达了编码PLP的人类cDNA，并在这个简单的异源系统中对该蛋白的亚细胞分布进行了表征。在当前研究中，我们采用相同的模式来研究PLP基因中的五个错义突变对编码蛋白加工过程的影响。所选择的突变跨越PLP的羧基末端一半，涵盖了已鉴定出大多数突变的蛋白区域。我们的结果表明，所有检测的突变体在分泌途径的早期阶段转运就被阻断，导致突变蛋白在内质网中积累。因此，蛋白错误折叠以及PLP无法到达少突胶质细胞表面的共同机制，而非突变蛋白无法在细胞表面执行某些关键功能，可能是许多PLP突变所导致疾病的原因。我们的结果以及其他人的结果促使我们推测，在PLP突变体中观察到的病理生物学现象可能是由于内质网中错误折叠蛋白的积累导致少突胶质细胞死亡所致。这一推测与以下观察结果一致：携带错误折叠PLP的少突胶质细胞，如在jimpy突变体中，会增殖但迅速死亡，而来自PLP缺失的少突胶质细胞则存活并产生缺乏PLP的髓鞘样膜。
