Professor Roland Brandt - Osnabrück University, Germany : "“From kiss-and-hop to aggregation: Targeting tau in the fight against neurodegeneration”
Speaker: Professor Roland Brandt
Osnabrück University
Germany
Title: “From kiss-and-hop to aggregation: Targeting tau in the fight against neurodegeneration”
Abstract:
Tauopathies such as Alzheimer’s disease are characterized by the aggregation of the microtubule-associated protein tau into neurofibrillary tangles composed of paired helical filaments (PHFs). The pathological changes of tau are closely linked to neurodegeneration, making tau a prime candidate for intervention. Using a live-cell imaging approach, we previously showed that tau interacts with axonal microtubules in a highly dynamic manner under physiological conditions, which we termed „kiss-and-hop“. Disease-associated changes of tau affect the interaction of tau with microtubules potentially inerfering with the physiological activity of tau. Using an aggregation-prone tau mutant, we developed an approach to monitor pathological changes and to screen for novel tau aggregation inhibitors in living neurons. Through chemoinformatic analysis, we identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau, inhibit tau aggregation, and restore physiological microtubule interaction of tau in neurons. Molecular dynamics simulations highlight cryptic channel-like pockets that cross tau protofilaments and show that binding of PHOX reduces the ability of the protofilaments to adopt a PHF-like conformation. We disucss how live cell imaging could contribute to identify compounds that inhibit tau aggregation in order to restore tau’s physiological function in disease.
Ref.: Janning et al. (2014) Single molecule tracking of tau reveals fast kiss-and-hop interaction with microtubules in living neurons. Mol. Biol. Cell 25:3541-3551; Conze et al. (2022) Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport. Mol. Psychiatry 27:3010-3023; Pinzi et al. (2022) Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule regulation. bioRxiv.
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