TY - JOUR T1 - A novel small molecule screening platform for disrupting toxic tau oligomers in cells JF - bioRxiv DO - 10.1101/510412 SP - 510412 AU - Chih Hung Lo AU - Colin Kin-Wye Lim AU - Zhipeng Ding AU - Sanjula Wickramasinghe AU - Anthony R. Braun AU - Elizabeth Rhoades AU - David D. Thomas AU - Jonathan N. Sachs Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/01/03/510412.abstract N2 - Tauopathies, including Alzheimer’s disease, are a group of neurodegenerative disorders characterized by pathological aggregation of the microtubule binding protein tau. Recent studies suggest that toxic tau oligomers, which are soluble and distinct from insoluble beta-sheet fibrils, are central players in neuronal cell death. To exploit this new therapeutic window, we engineered two first-in-class FRET based biosensors that monitor tau conformations in cells. Because this new technology platform operates in cells, it enables high-throughput screening of small molecules that target tau oligomers while avoiding the uncertainties of idiosyncratic in vitro preparations of tau assemblies from purified protein. We found a small molecule, MK-886, that disrupts tau oligomers and reduces tau-induced cell cytotoxicity with nanomolar potency. Using SPR and an advanced single-molecule FRET technique, we show that MK-886 directly binds to tau and specifically perturbs the folding of tau monomer in the proline-rich and microtubule-binding regions. Furthermore, we show that MK-886 accelerates the tau aggregation lag phase using a thioflavin-T assay, implying that the compound stabilizes a non-toxic, on-pathway oligomer. The technology described here should generalize to the study and targeting of conformational ensembles within the aggregation pathways of most intrinsically disordered proteins. ER -