Oxidative modification alters tau condensation and promotes tau-associated cytoplasmic speckle formation.

Oxidative modification-mediated tau aggregation is believed to contribute to multiple aging-related neurodegenerative diseases. Significant evidence indicates that various aging disease-related aggregates are closely linked to biochemical modification-driven abnormal protein phase separation, a thermodynamic conversion to form biomolecular and functional condensates, which are commonly named membrane-less organelles. However, whether oxidative modification regulates tau phase separation remains elusive. In the present study, we show that oxidative modification of cysteine 291 and cysteine 322 in tau impairs the liquidity of tau condensates in vitro and in cells, and promotes mis-localization of SRRM2 and SRSF2, the pre-mRNA splicing-related nuclear speckle protein, to cytoplasmic tau aggregates to form tau-associated cytoplasmic speckle (TACS). Interestingly and importantly, we found that RING-Bait technology, which has been shown to selectively target and clear protein aggregates, will be helpful for the elimination of TACS upon oxidative stress exposure. Taken together, our study illustrates the role of oxidative modification in tau phase separation and TACS formation and provides a novel therapeutic strategy for oxidative stress-associated aging-related neurodegenerative diseases.