Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

TitleHuman iPSC 4R tauopathy model uncovers modifiers of tau propagation.
Publication TypeJournal Article
Year of Publication2023
AuthorsBravo CParra, Giani AMaria, Perez JMadero, Zhao Z, Samelson A, Wong MYing, Evangelisti A, Fan L, Pozner T, Mercedes M, Ye P, Patel T, Yarahmady A, Carling G, M Y Lee V, Sharma M, Mok S-A, Luo W, Zhao M, Kampmann M, Gong S, Gan L
Date Published2023 Jun 22

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.

Alternate JournalbioRxiv
PubMed ID37745431
PubMed Central IDPMC10516028