| First Author | Parra Bravo C | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 10 | Pages | 2446-2464.e22 |
| PubMed ID | 38582079 | Mgi Jnum | J:348746 |
| Mgi Id | MGI:7639530 | Doi | 10.1016/j.cell.2024.03.015 |
| Citation | Parra Bravo C, et al. (2024) Human iPSC 4R tauopathy model uncovers modifiers of tau propagation. Cell 187(10):2446-2464.e22 |
| abstractText | 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. |
