Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum.
Disease-associated mutations cause premature oligomerization of myelin proteolipid protein in the endoplasmic reticulum.
复制标题
疾病相关突变导致内质网中髓磷脂蛋白脂质蛋白过早寡聚化。
DOI：
10.1073/pnas.0407287102
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发表时间：
2005
影响因子：
11.1
通讯作者：
P. Woodman
中科院分区：
文献类型：
--
作者：
E. Swanton;A. Holland;S. High;P. Woodman
Pelizaeus-Merzbacher病（PMD）是由蛋白脂质蛋白（PLP）基因的突变、缺失或重复引起的髓鞘形成障碍疾病。PLP的突变形式保留在内质网（ER）中，并且由此产生的突变蛋白的积累被认为是少突胶质细胞死亡的直接原因，少突胶质细胞死亡是PMD的主要临床特征。然而，突变体PLP毒性的分子机制目前尚不清楚。我们在这里报告，PMD连锁突变的PLP与加速组装成稳定的同源寡聚体，类似于成熟的，天然的PLP蛋白。因此，尽管WT PLP在延长的成熟期后最可能在细胞表面形成稳定的寡聚体，但PLP的突变形式在ER处迅速组装成此类寡聚体。使用与不同严重程度的疾病相关的PLP突变体，我们表明稳定的寡聚体的形成与PMD的发展相关。基于这些发现，我们提出，PLP在少突胶质细胞ER中的过早寡聚化有助于PMD的病理。
Pelizaeus-Merzbacher disease (PMD) is a dysmyelinating disease caused by mutations, deletions, or duplications of the proteolipid protein (PLP) gene. Mutant forms of PLP are retained in the endoplasmic reticulum (ER), and the resulting accumulation of mutant protein is thought to be a direct cause of oligodendrocyte cell death, which is the primary clinical feature of PMD. The molecular mechanisms underlying the toxicity of mutant PLP are however currently unknown. We report here that PMD-linked mutations of PLP are associated with the accelerated assembly of the protein into stable homooligomers that resemble mature, native PLP. Thus although WT PLP forms stable oligomers after an extended maturation period, most likely at the cell surface, mutant forms of PLP rapidly assemble into such oligomers at the ER. Using PLP mutants associated with diseases of varying severity, we show that the formation of stable oligomers correlates with the development of PMD. Based on these findings, we propose that the premature oligomerization of PLP in the ER of oligodendrocytes contributes to the pathology of PMD.