Cellular Pathology of Pelizaeus-Merzbacher Disease Involving Chaperones Associated with Endoplasmic Reticulum Stress.
Cellular Pathology of Pelizaeus-Merzbacher Disease Involving Chaperones Associated with Endoplasmic Reticulum Stress.
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DOI：
10.3389/fmolb.2017.00007
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发表时间：
2017
影响因子：
5
通讯作者：
Inoue K
中科院分区：
文献类型：
--
作者：
Inoue K
编码膜蛋白的基因中的致病突变可导致在内质网（ER）中积累的异常多肽的产生。这些突变蛋白具有有害的构象变化或错误折叠事件，其导致未折叠蛋白反应（UPR）的触发。UPR是一种细胞途径，其通常通过抑制翻译、增加ER伴侣水平或在严重ER应激中诱导细胞凋亡来降低ER应激。这一过程涉及许多神经系统疾病的细胞病理学，包括Pelizaeus-Merzbacher病（PMD）。PMD是一种罕见的儿科疾病，其特征在于中枢神经系统（CNS）髓鞘形成过程的失败。PMD是由编码主要髓鞘膜蛋白的PLP 1基因突变引起的。严重的临床PMD表型似乎是细胞毒性的结果，由于PLP 1突变蛋白的积累，而不是由于缺乏功能性PLP 1。因此，重要的是要澄清PLP 1突变体对髓鞘生成细胞（称为少突胶质细胞）产生负面影响的病理机制，以克服这种破坏性疾病。本文综述了PLP 1突变蛋白如何改变少突胶质细胞内质网中蛋白质的稳态，特别关注内质网伴侣对导致PMD的PLP 1突变蛋白积累的反应。
Disease-causing mutations in genes encoding membrane proteins may lead to the production of aberrant polypeptides that accumulate in the endoplasmic reticulum (ER). These mutant proteins have detrimental conformational changes or misfolding events, which result in the triggering of the unfolded protein response (UPR). UPR is a cellular pathway that reduces ER stress by generally inhibiting translation, increasing ER chaperones levels, or inducing cell apoptosis in severe ER stress. This process has been implicated in the cellular pathology of many neurological disorders, including Pelizaeus-Merzbacher disease (PMD). PMD is a rare pediatric disorder characterized by the failure in the myelination process of the central nervous system (CNS). PMD is caused by mutations in the PLP1 gene, which encodes a major myelin membrane protein. Severe clinical PMD phenotypes appear to be the result of cell toxicity, due to the accumulation of PLP1 mutant proteins and not due to the lack of functional PLP1. Therefore, it is important to clarify the pathological mechanisms by which the PLP1 mutants negatively impact the myelin-generating cells, called oligodendrocytes, to overcome this devastating disease. This review discusses how PLP1 mutant proteins change protein homeostasis in the ER of oligodendrocytes, especially focusing on the reaction of ER chaperones against the accumulation of PLP1 mutant proteins that cause PMD.