The Role of JADE1 in Tauopathy

The goal of the project is to advance our mechanistic understanding of tau pathology by characterizing the ability of JADE1S to modulate tau protein homeostasis and aggregation in vitro.

Tauopathies, such as Alzheimer’s disease, result from the toxic aggregation of tau proteins, but the exact process remains unclear. We are investigating JADE1, a protein that specifically binds toxic tau, to determine if it prevents aggregation or promotes clearance via cellular pathways like autophagy. Using advanced cellular models, including one that uses light to control tau behavior, our research aims to uncover how JADE1 works and explore its potential as a target for future treatments.

Our approach focusing on JADE1, which potentially specifically targets the toxic 4R tau species, is a departure from other studies. A better understanding of JADE1 has the potential to be relevant not only for Alzheimer’s disease, but for tauopathies in general. We will use proteomics, NMR spectroscopy, and an innovative optogenetic system that models condensate formation involved in tau aggregation. This approach enables reproducible study of early tau aggregation events and real-time comparison of wild-type and mutant isoforms.

This study will establish JADE1S’s role in selective 4R tau clearance, providing critical evidence for isoform-specific regulatory mechanisms and new therapeutic targets for tauopathies. Our data on JADE1–tau interaction will offer a molecular foothold for therapeutic development targeting binding sites with peptides, small molecules, intrabodies, or PROTACs. This approach aims to launch further studies of candidate mechanisms and advance potential therapeutic interventions.