Fluorescence imaging-based investigation of tau-mediated promotion of U1 small nuclear ribonucleoprotein 70 kDa co-phase separation.

Neurofibrillary tangles formed by Tau protein are a core pathological hallmark of Alzheimer's disease (AD). Although liquid-liquid phase separation (LLPS) of Tau is thought to induce its aggregation, and the basic-acidic dipeptide (BAD) domain-containing protein U1 small nuclear ribonucleoprotein 70 kDa (U1-70K) abnormally co-localizes with Tau tangles in AD brains, the molecular mechanism underlying their co-aggregation remains unclear. In this study, we found that Tau co-phase separates with two low-complexity domains (LC1/LC2). Both LC1 and LC2 promote the gelation of Tau droplets and the formation of pathological Tau aggregates under the conditions tested. Furthermore, under cellular stress, Tau and U1-70K exhibit aberrant cytoplasmic co-localization, suggesting a functional link between them under pathological conditions and providing new insights into the molecular basis of Tau pathology in AD.