Abstract：
Familial neurohypophyseal diabetes insipidus (FNDI) is a degenerative disorder in which vasopressin-secreting neurons degenerate over time due to the production of mutant proteins. We have demonstrated therapeutic effects of chemical chaperones in an FNDI mouse model, but the complexity and length of this evaluation were problematic. In this study, we established disease-specific mouse induced pluripotent stem cells (iPSCs) from FNDI-model mice and differentiated vasopressin neurons that produced mutant proteins. Fluorescence immunostaining showed that chemical chaperones appeared to protect vasopressin neurons generated from iPSCs derived from FNDI-model mice. Although KCL stimulation released vasopressin hormone from vasopressin neurons generated from FNDI-derived iPSCs, vasopressin hormone levels did not differ significantly between baseline and chaperone-added culture. Semi-quantification of vasopressin carrier protein and mutant protein volumes in vasopressin neurons confirmed that chaperones exerted a therapeutic effect. This research provides fundamental technology for creating in vitro disease models using human iPSCs and can be applied to therapeutic evaluation of various degenerative diseases that produce abnormal proteins.
摘要：
家族性神经垂体尿崩症（FNDI）是一种退行性疾病，其中分泌加压素的神经元由于突变蛋白的产生而随时间退化。我们已经证明了化学伴侣在FNDI小鼠模型中的治疗效果，但是这种评估的复杂性和长度是有问题的。在这项研究中,我们从FNDI模型小鼠中建立了疾病特异性小鼠诱导多能干细胞(iPSCs),并分化了产生突变蛋白的加压素神经元.荧光免疫染色显示化学伴侣似乎保护由源自FNDI模型小鼠的iPSC产生的加压素神经元。尽管KCL刺激从FNDI来源的iPSC产生的加压素神经元释放了加压素激素，加压素激素水平在基线和添加伴侣培养之间没有显著差异.加压素载体蛋白和加压素神经元中突变蛋白体积的半定量证实了伴侣发挥治疗作用。这项研究为使用人iPSC创建体外疾病模型提供了基础技术，可应用于产生异常蛋白质的各种退行性疾病的治疗性评估。
