Tauopathies are neurodegenerative diseases characterized by the accumulation of aggregates of the microtubule-associated protein tau. They can be divided into three subtypes (3R, 4R and 3R/4R), each exhibiting tau filaments with different structures that contain tau isoforms with three (3R) and/or four (4R) microtubule-binding repeats. In Cell, Parra Bravo et al. report neuronal lines derived from human induced pluripotent stem (iPS) cells that can be used as robust models for 4R tauopathies and, using such models, they uncover UFMylation as an important regulator of tau propagation.

Using an antibody that specifically recognizes pathogenic tau from human patients, the authors analysed the formation of insoluble tau inclusions in 4R and 4R-P301S neurons. When aggregation-inducing fibrils were added to the growth medium, this triggered the formation of inclusions via a prion-like propagation mechanism, similar to template-induced propagation of misfolded proteins, in 4R-P301S neurons but not in 4R neurons. RNA-sequencing analyses identified genes that are differentially expressed in the tau-seeded inclusion-containing 4R-P301S neurons, and similarities with gene expression profiles of postmortem human Alzheimer disease brains were found, thus validating the in vitro model.