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Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

2024; Cell Press; Volume: 187; Issue: 10 Linguagem: Inglês

10.1016/j.cell.2024.03.015

1097-4172

C 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 Mercédes, Tark Patel, Allan Yarahmady, Gillian Carling, Fredrik 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,

Medicinal Plants and Neuroprotection

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.