Abnormal synaptic architecture in iPSC-derived neurons from a multi-generational family with genetic Creutzfeldt-Jakob disease.

IF 5.9 2区 医学 Q1 CELL & TISSUE ENGINEERING
Stem Cell Reports Pub Date : 2024-10-08 Epub Date: 2024-09-26 DOI:10.1016/j.stemcr.2024.08.010
Aldana D Gojanovich, Nhat T T Le, Robert C C Mercer, Seonmi Park, Bei Wu, Alice Anane, Janelle S Vultaggio, Gustavo Mostoslavsky, David A Harris
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引用次数: 0

Abstract

Genetic prion diseases are caused by mutations in PRNP, which encodes the prion protein (PrPC). Why these mutations are pathogenic, and how they alter the properties of PrPC are poorly understood. We have consented and accessed 22 individuals of a multi-generational Israeli family harboring the highly penetrant E200K PRNP mutation and generated a library of induced pluripotent stem cells (iPSCs) representing nine carriers and four non-carriers. iPSC-derived neurons from E200K carriers display abnormal synaptic architecture characterized by misalignment of postsynaptic NMDA receptors with the cytoplasmic scaffolding protein PSD95. Differentiated neurons from mutation carriers do not produce PrPSc, the aggregated and infectious conformer of PrP, suggesting that loss of a physiological function of PrPC may contribute to the disease phenotype. Our study shows that iPSC-derived neurons can provide important mechanistic insights into the pathogenesis of genetic prion diseases and can offer a powerful platform for testing candidate therapeutics.

遗传性克雅氏病多代家族 iPSC 衍生神经元的异常突触结构。
遗传性朊病毒疾病是由编码朊病毒蛋白(PrPC)的 PRNP 基因突变引起的。人们对这些突变为何致病以及它们如何改变 PrPC 的特性知之甚少。我们同意并访问了一个以色列多代家族中携带高渗透性 E200K PRNP 突变的 22 个个体,并生成了一个诱导多能干细胞(iPSC)库,其中 9 个为携带者,4 个为非携带者。来自 E200K 携带者的 iPSC 衍生神经元显示出异常的突触结构,其特征是突触后 NMDA 受体与细胞质支架蛋白 PSD95 错位。突变携带者的分化神经元不会产生 PrPSc(PrP 的聚集和感染性构象),这表明 PrPC 生理功能的缺失可能是导致疾病表型的原因之一。我们的研究表明,iPSC衍生神经元可为遗传性朊病毒疾病的发病机制提供重要的机理见解,并可为测试候选疗法提供一个强大的平台。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Stem Cell Reports
Stem Cell Reports CELL & TISSUE ENGINEERING-CELL BIOLOGY
CiteScore
10.50
自引率
1.70%
发文量
200
审稿时长
28 weeks
期刊介绍: Stem Cell Reports publishes high-quality, peer-reviewed research presenting conceptual or practical advances across the breadth of stem cell research and its applications to medicine. Our particular focus on shorter, single-point articles, timely publication, strong editorial decision-making and scientific input by leaders in the field and a "scoop protection" mechanism are reasons to submit your best papers.
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