Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes.
Involvement of ER stress in dysmyelination of Pelizaeus-Merzbacher Disease with PLP1 missense mutations shown by iPSC-derived oligodendrocytes.
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DOI：
10.1016/j.stemcr.2014.03.007
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发表时间：
2014-05-06
影响因子：
5.9
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Numasawa-Kuroiwa, Yuko;Okada, Yohei;Shibata, Shinsuke;Kishi, Noriyuki;Akamatsu, Wado;Shoji, Masanobu;Nakanishi, Atsushi;Oyama, Manabu;Osaka, Hitoshi;Inoue, Ken;Takahashi, Kazutoshi;Yamanaka, Shinya;Kosaki, Kenjiro;Takahashi, Takao;Okano, Hideyuki
Pelizaeus-Merzbacher病（PMD）是一种由蛋白脂质蛋白1（PLP 1）基因突变引起的X连锁脑白质营养不良。虽然错义突变的PLP 1蛋白质已被证明在疾病模型动物和突变PLP 1基因转染的细胞系中的粗面内质网（ER）中积累，但PMD的确切发病机制尚未阐明。本研究从两名PMD患者体内分离出错义突变的诱导多能干细胞，并在体外诱导其分化为少突胶质细胞。在PMD iPSC衍生的少突胶质细胞中，观察到突变体PLP 1蛋白与ER的错误定位以及对ER应激的敏感性增加与凋亡少突胶质细胞数量增加之间的关联。此外，电子显微镜分析表明，髓鞘形成急剧减少伴随着异常的ER形态。因此，本研究表明ER应激参与了PLP 1错义突变PMD患者少突胶质细胞的致病性髓鞘形成障碍。使用iPSC衍生的少突胶质细胞建模Pelizaeus-Merzbacher病（PMD）增加的ER应激参与PMD iPSC衍生的少突胶质细胞的凋亡PMD iPSC衍生的少突胶质细胞中的异常髓鞘结构和ER形态髓鞘形成障碍疾病的病理生理学模型Pelizaeus-Merzbacher病（PMD）是由蛋白脂质蛋白1（PLP 1）基因突变引起的X连锁脑白质营养不良的一种形式。Okano，Okada及其同事从两名携带PLP 1错义突变的PMD患者中建立了iPSCs，在体外将其分化为少突胶质细胞，并证明ER应激参与了致病性髓鞘形成障碍。该模型可用于髓鞘发育障碍性神经系统疾病的病理生理学分析。
Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Although PLP1 proteins with missense mutations have been shown to accumulate in the rough endoplasmic reticulum (ER) in disease model animals and cell lines transfected with mutant PLP1 genes, the exact pathogenetic mechanism of PMD has not previously been clarified. In this study, we established induced pluripotent stem cells (iPSCs) from two PMD patients carrying missense mutation and differentiated them into oligodendrocytes in vitro. In the PMD iPSC-derived oligodendrocytes, mislocalization of mutant PLP1 proteins to the ER and an association between increased susceptibility to ER stress and increased numbers of apoptotic oligodendrocytes were observed. Moreover, electron microscopic analysis demonstrated drastically reduced myelin formation accompanied by abnormal ER morphology. Thus, this study demonstrates the involvement of ER stress in pathogenic dysmyelination in the oligodendrocytes of PMD patients with the PLP1 missense mutation. Modeling Pelizaeus-Merzbacher disease (PMD) using iPSC-derived oligodendrocytes Increased ER stress involved in the apoptosis of PMD iPSC-derived oligodendrocytes Abnormal myelin structures and ER morphologies in PMD iPSC-derived oligodendrocytes Models for the pathophysiology of dysmyelinating disorders Pelizaeus-Merzbacher disease (PMD) is a form of X-linked leukodystrophy caused by mutations in the proteolipid protein 1 (PLP1) gene. Okano, Okada, and colleagues established iPSCs from two PMD patients carrying PLP1 missense mutation, differentiated them into oligodendrocytes in vitro, and demonstrated the involvement of ER stress in the pathogenic dysmyelination. This model is useful for the pathophysiological analysis of dysmyelinating neurological disorders.
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影响因子：
2.7
作者：
Okada, Y;Shimazaki, T;Okano, H
通讯作者：
Okano, H
影响因子：
5.2
作者：
Okada, Yohei;Matsumoto, Arifumi;Okano, Hideyuki
通讯作者：
Okano, Hideyuki
影响因子：
4.2
作者：
GOW, A;FRIEDRICH, VL;LAZZARINI, RA
通讯作者：
LAZZARINI, RA
影响因子：
16.2
作者：
Southwood, CM;Garbern, J;Gow, A
通讯作者：
Gow, A
影响因子：
3.7
作者：
Ohta S;Imaizumi Y;Okada Y;Akamatsu W;Kuwahara R;Ohyama M;Amagai M;Matsuzaki Y;Yamanaka S;Okano H;Kawakami Y
通讯作者：
Kawakami Y