Aberrant TDP-43 phase transitions, which are primed by oxidative stress and chaperone inhibition, command molecular malfunction in several neurodegenerative diseases.

 The RNA binding protein TDP-43 forms cytoplasmic pathological inclusions which are triggered by its C-terminal prion-like domain. Increasing evidence indicates that cytotoxicity is caused by aberrancies in TDP-43 phase de-mixing rather than aggregation. However, since TDP-43 forms abundant reversible stress granules in stressful conditions, questions arise regarding the factors that separate functional from aberrant phase separation. In collaboration with scientists from CBM-SO (CSIC) and U. Hong Kong, researchers from Rocasolano Institute have determined that metamorphism in TDP-43 prion-like domain impacts the interactome and prompts alternative accumulative traits. In particular, methionine sulfoxidation, which accumulates under oxidative stress due to redox homeostasis impairment, hinders phase separation, promotes alternative amyloid structures, abrogates chaperone recognition and alters phosphorylation by casein kinase-1d. Our data shows that metamorphism in the modified TDP-43 prion like domain favor mechanisms with major relevance in disease, and stress the importance of including the relevant post-translationally modified chains as the targets for disease intervention. https://doi.org/10.1038/s41467-023-36023-z