Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

Parra Bravo, C.; Giani, A. M.; Madero-Perez, J.; Zhao, Z.; Samelson, A. J.; Wong, M. Y.; Evangelisti, A.; Fan, L.; Pozner, T.; Mercedes, M.; Ye, P.; Patel, T.; Yarahmady, A.; Carling, G.; Lee, V. M. Y.; Sharma, M.; Mok, S.-A.; Luo, W.; Zhao, M.; Kampmann, M.; Gong, S.; Gan, L.

doi:10.1101/2023.06.19.544278

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bioRxiv · 10.1101/2023.06.19.544278

Human iPSC 4R tauopathy model uncovers modifiers of tau propagation

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Abstract

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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Parra Bravo, C., Giani, A. M., Madero-Perez, J., Zhao, Z., Samelson, A. J., Wong, M. Y., Evangelisti, A., Fan, L., Pozner, T., Mercedes, M., Ye, P., Patel, T., Yarahmady, A., Carling, G., Lee, V. M. Y., Sharma, M., Mok, S.-A., Luo, W., Zhao, M., Kampmann, M., Gong, S., Gan, L.. 2023-06-22. Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. https://doi.org/10.1101/2023.06.19.544278

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