Generation and characterization of human iPSC-derived NPC1I1061T/I10161T i3Neurons as a model for NPC1 disease

This manuscript describes the generation of an inducible pluripotent stem cell (iPSC) line expressing a mutant form of NPC1. This variant, NPC1(I1061T/I1061T), represents a common pathogenic variant of NPC1 in NPC1 affected individuals. Upon differentiation of the iPSCs into i3Neurons, we characterized the cellular phenotype with respect to gycosylation of NPC1, accumulation of free cholesterol, and response to known therapeutics. The results demonstrate that this cell line exhibits the expected characteristics of the NPC1(I1061/I1061T) mutant protein resulting in an NPC1 disease phenotype in these cells. This new cell line can be used as a neuronal model of Niemann-Pick disease, type C1.本文描述了一株表达突变型尼曼-匹克C1蛋白（NPC1）的诱导多能干细胞（inducible pluripotent stem cell, iPSC）系的构建过程。该突变体NPC1(I1061T/I1061T)是尼曼-匹克C1型疾病（Niemann-Pick disease, type C1）患者中常见的NPC1致病突变。将该iPSC诱导分化为i3Neurons后，我们从NPC1糖基化水平、游离胆固醇蓄积情况以及对已知治疗药物的响应三个方面对其细胞表型进行了表征。实验结果证实，该细胞系呈现出NPC1(I1061/I1061T)突变蛋白的预期特征，进而使细胞产生NPC1疾病表型。该新型细胞系可作为尼曼-匹克C1型疾病的神经元模型。