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 Publication2024
AuthorsBravo CParra, Giani AMaria, Perez JMadero, Zhao Z, Wan Y, Samelson AJ, Wong MYing, Evangelisti A, Cordes E, Fan L, Ye P, Zhu D, Pozner T, Mercedes M, Patel T, Yarahmady A, Carling GK, Sterky FH, M Y Lee V, Lee EB, DeTure M, Dickson DW, Sharma M, Mok S-A, Luo W, Zhao M, Kampmann M, Gong S, Gan L
Date Published2024 Mar 28

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.

Alternate JournalCell
PubMed ID38582079