Saito Ryo, Miyajima Takashi, Iwamoto Takeo, Wu Chen, Suzuki Ken, Hossain Mohammad Arif, Munakata Miyo, Era Takumi, Eto Yoshikatsu
Advanced Clinical Research Center, Southern Tohoku Research Institute for Neuroscience, 255 Furusawa, Asao-ku, Kawasaki 215-0026, Japan.
Core Research Facilities for Basic Science, The Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan.
Mol Genet Metab Rep. 2021 Jul 24;28:100784. doi: 10.1016/j.ymgmr.2021.100784. eCollection 2021 Sep.
Niemann-Pick disease type C (NPC) is a rare neurodegenerative disorder caused by a recessive mutation in the or 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.
尼曼-匹克病C型（NPC）是一种罕见的神经退行性疾病，由 或 基因的隐性突变引起，患者表现出溶酶体中未酯化胆固醇和糖脂的积累。大多数关于NPC的研究是在患者来源的皮肤成纤维细胞或小鼠模型中进行的。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）中均观察到了NPC特有的胆固醇和糖脂积累，但我们在这些未成熟细胞中未观察到分化潜能和自噬活性的异常。然而，在源自NPC患者的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。通过脂滴鉴定的胆固醇和其他脂质的异常积累以及溶酶体数量的增加在成熟神经元细胞中比在iPSC和/或NSC中更为突出。超薄切片电子显微镜分析还显示成熟神经元细胞中有许多典型的膜性细胞质体。此外，源自NPC患者的神经元细胞中TUJ1阳性神经突密度显著降低。此外，源自NPC患者的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，源自NPC患者的成熟神经元细胞中与神经退行性变相关的神经网络形成受损。
