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A neuropathological cell model derived from Niemann−Pick disease type C patient-specific iPSCs shows disruption of the p62/SQSTM1−KEAP1−NRF2 Axis and impaired formation of neuronal networks
Molecular Genetics and Metabolism Reports ( IF 1.8 ) Pub Date : 2021-07-24 , DOI: 10.1016/j.ymgmr.2021.100784
Ryo Saito 1, 2 , Takashi Miyajima 1, 3 , Takeo Iwamoto 1, 2 , Chen Wu 1, 3 , Ken Suzuki 1 , Mohammad Arif Hossain 1, 2 , Miyo Munakata 4 , Takumi Era 5 , Yoshikatsu Eto 1, 4, 6
Affiliation  

Niemann−Pick disease type C (NPC) is a rare neurodegenerative disorder caused by a recessive mutation in the NPC1 or NPC2 gene, in which patients exhibit lysosomal accumulation of unesterified cholesterol and glycolipids. Most of the research on NPC has been done in patient-derived skin fibroblasts or mouse models. Therefore, we developed NPC patient neurons derived from induced pluripotent stem cells (iPSCs) to investigate the neuropathological cause of the disease. Although an accumulation of cholesterol and glycolipids, which is characteristic of NPC, was observed in both undifferentiated iPSCs and derived neural stem cells (NSCs), we could not observed the abnormalities in differentiation potential and autophagic activity in such immature cells. However, definite neuropathological features were detected in mature neuronal cells generated from NPC patient-derived iPSCs. Abnormal accumulation of cholesterol and other lipids identified by lipid droplets and number of enlarged lysosomes was more prominent in mature neuronal cells rather than in iPSCs and/or NSCs. Thin-sectioning electron microscopic analysis also demonstrated numerous typical membranous cytoplasmic bodies in mature neuronal cells. Furthermore, TUJ1-positive neurite density was significantly reduced in NPC patient-derived neuronal cells. In addition, disruption of the p62/SQSTM1−KEAP1−NRF2 axis occurred in neurons differentiated from NPC patient-derived iPSCs. These data indicate the impairment of neuronal network formation associated with neurodegeneration in mature neuronal cells derived from patients with NPC.



中文翻译:

源自 Niemann-Pick 病 C 型患者特异性 iPSC 的神经病理学细胞模型显示 p62/SQSTM1-KEAP1-NRF2 轴的破坏和神经元网络的形成受损

Niemann-Pick 病 C 型 (NPC) 是一种罕见的神经退行性疾病,由NPC1NPC2的隐性突变引起基因,其中患者表现出未酯化的胆固醇和糖脂的溶酶体积累。大多数关于 NPC 的研究都是在患者来源的皮肤成纤维细胞或小鼠模型中完成的。因此,我们开发了源自​​诱导多能干细胞 (iPSC) 的 NPC 患者神经元,以研究该疾病的神经病理学原因。尽管在未分化的 iPSC 和衍生的神经干细胞 (NSC) 中都观察到胆固醇和糖脂的积累,这是 NPC 的特征,但我们无法观察到这种未成熟细胞的分化潜能和自噬活性异常。然而,在 NPC 患者来源的 iPSC 产生的成熟神经元细胞中检测到了明确的神经病理学特征。由脂滴和溶酶体数量增加确定的胆固醇和其他脂质的异常积累在成熟神经元细胞中更为突出,而不是在 iPSC 和/或 NSC 中。薄切片电子显微镜分析还表明成熟神经元细胞中有许多典型的膜质细胞质体。此外,鼻咽癌患者来源的神经元细胞中的 TUJ1 阳性神经突密度显着降低。此外,从 NPC 患者来源的 iPSC 分化的神经元中发生了 p62/SQSTM1-KEAP1-NRF2 轴的破坏。这些数据表明,在源自 NPC 患者的成熟神经元细胞中,与神经变性相关的神经元网络形成受损。薄切片电子显微镜分析还表明成熟神经元细胞中有许多典型的膜质细胞质体。此外,鼻咽癌患者来源的神经元细胞中的 TUJ1 阳性神经突密度显着降低。此外,从 NPC 患者来源的 iPSC 分化的神经元中发生了 p62/SQSTM1-KEAP1-NRF2 轴的破坏。这些数据表明,在源自 NPC 患者的成熟神经元细胞中,与神经变性相关的神经元网络形成受损。薄切片电子显微镜分析还表明成熟神经元细胞中有许多典型的膜质细胞质体。此外,鼻咽癌患者来源的神经元细胞中的 TUJ1 阳性神经突密度显着降低。此外,从 NPC 患者来源的 iPSC 分化的神经元中发生了 p62/SQSTM1-KEAP1-NRF2 轴的破坏。这些数据表明,在源自 NPC 患者的成熟神经元细胞中,与神经变性相关的神经元网络形成受损。

更新日期:2021-07-25
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