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

卷:28

Takashi Miyajima¹  Miyo Munakata¹  Takeo Iwamoto²  Yoshikatsu Eto³  Ken Suzuki³  Takumi Era⁴  Chen Wu⁴  Ryo Saito⁴  Mohammad Arif Hossain⁴ 

[1] Core Research Facilities for Basic Science, The Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan;

[2] Corresponding authors at: Advanced Clinical Research Center, Southern Tohoku Research Institute for Neuroscience, 255 Furusawa, Asao-ku, Kawasaki 215-0026, Japan.;

[3] Rare disease research center, AnGes Inc., 127 Furusawa, Asao-ku, Kawasaki 215-0026, Japan;

[4] Advanced Clinical Research Center, Southern Tohoku Research Institute for Neuroscience, 255 Furusawa, Asao-ku, Kawasaki 215-0026, Japan;

关键词: Niemann−Pick disease type C;    Lysosomal storage disorder;    Induced pluripotent stem cells;    Cell-based neuropathological model;    Neuronal network density;    p62/SQSTM1−KEAP1−NRF2 axis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown