美国威尔康奈尔医学院Li Gan等研究人员合作发现，人类iPSC 4R Tau病理模型揭示Tau传播的调节因子。2024年4月5日，《细胞》杂志在线发表了这项成果。
研究人员改造了人类诱导多能干细胞（hiPSC）衍生的神经元谱系，使其在分化成神经元时表达4R Tau和携带P301S MAPT突变的4R Tau。4R-P301S神经元在播种Tau纤维后显示出渐进的Tau包涵体，并再现了Tau病理表型的特征，包括共享的转录组特征、自噬体积累和神经元活性降低。
通过CRISPRi筛选与Tau病理生物学相关的基因，研究人员发现了500多个种子诱导Tau传播的遗传修饰因子，包括逆运复合体VPS29和UFMylation级联中的基因。在进行性核上性麻痹（PSP）和阿尔茨海默病（AD）大脑中，神经纤维缠结神经元的UFMylation级联发生了改变。在体外和体内抑制UFMylation级联可抑制种子诱导的Tau传播。该模型为确定4R Tau病理的新型治疗策略提供了一个强大的平台。
据悉，au病理是一种与年龄相关的神经退行性疾病，其机理基础仍然难以捉摸，部分原因是缺乏合适的人类模型。
附：英文原文
Title: Human iPSC 4R tauopathy model uncovers modifiers of tau propagation
Author: Celeste Parra Bravo, Alice Maria Giani, Jesus Madero Perez, Zeping Zhao, Yuansong Wan, Avi J. Samelson, Man Ying Wong, Alessandro Evangelisti, Ethan Cordes, Li Fan, Pearly Ye, Daphne Zhu, Tatyana Pozner, Maria Mercedes, Tark Patel, Allan Yarahmady, Gillian K. Carling, Fredrik H. Sterky, Virginia M.Y. Lee, Edward B. Lee, Michael DeTure, Dennis W. Dickson, Manu Sharma, Sue-Ann Mok, Wenjie Luo, Mingrui Zhao, Martin Kampmann, Shiaoching Gong, Li Gan
Issue&Volume: 2024-04-05
Abstract: Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer’s Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.
DOI: 10.1016/j.cell.2024.03.015
Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00306-4