Zhang, J., Hu, J., Liu, R., Zhou, T., Luo, X., Liang, P., Xie, Z., Zhao, Q., Chen, Y., Du, D., Liu, C., Zheng, Y., Li, D., Wang, B. (2025). YAP maintains the dynamics of TDP-43 condensates and antagonizes TDP-43 pathological aggregates.  Nat. Cell Biol. 27(7): 1148--1160.

FBrf0262945

Research paper

Recent studies exploring the underlying pathomechanisms of amyotrophic lateral sclerosis (ALS), a fatal motor neuron disorder, have focused on biomolecular condensates. Here we reveal an unexpected function for YAP, a central component of the Hippo pathway, in regulating the dynamic behaviour of stress granules and TDP-43 condensates, a role that is independent of its transcriptional activity in the Hippo pathway. YAP directly binds to TDP-43. This interaction directly promotes the homotypic multimerization and phase separation of TDP-43 while inhibiting its hyperphosphorylation and solidification under stress conditions. Remarkably, YAP, whose messenger RNA levels are reduced in patients with ALS, is found to co-localize with pathological hyperphosphorylated TDP-43 aggregates in the brains of patients with ALS. In addition, elevation of YAP/Yorkie (a fly homologue of mammalian YAP) expression substantially reduces TDP-43 toxicity in primary neuron and transgenic fly models of ALS. Our findings highlight an unexpected role of YAP in managing ALS-associated biomolecular condensates, presenting important implications for potential ALS treatments.