陶氏病
纠纷
τ蛋白
神经科学
诱导多能干细胞
生物
表型
细胞生物学
基因
神经退行性变
遗传学
阿尔茨海默病
疾病
医学
胚胎干细胞
数学
病理
纯数学
作者
Concepción Bravo,Alice Maria Giani,Jesús Madero-Pérez,Zeping Zhao,Avi J. Samelson,Man Ying Wong,Alessandro Evangelisti,Li Fan,Tatyana Pozner,María Mercedes,Pearly Ye,Tark Patel,Allan Yarahmady,Gillian Carling,Virginia M.‐Y. Lee,Manu Sharma,Sue-Ann Mok,Wenjie Luo,Mingrui Zhao,Martin Kampmann,Shiaoching Gong,Li Gan
标识
DOI:10.1101/2023.06.19.544278
摘要
Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to lack of appropriate human models. Current human induced pluripotent stem cell (hiPSC)-derived neurons express very low levels of 4-repeat (4R)-tau isoforms that are normally expressed in adult brain. Here, we engineered new iPSC 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 impaired neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of Tau-seeding-induced Tau propagation, including retromer VPS29 and the UFMylation cascade as top modifiers. In AD brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade suppressed seeding-induced Tau propagation. This model provides a powerful platform to identify novel therapeutic strategies for 4R tauopathy.
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