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Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction

Pinzi, Luca; Conze, Christian; Bisi, Nicolo; Torre, Gabriele Dalla; Soliman, Ahmed; Monteiro-Abreu, Nanci; Trushina, Nataliya I; ... Brandt, Roland; + view all (2024) Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction. Nature Communications , 15 , Article 1679. 10.1038/s41467-024-45851-6. Green open access

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Abstract

Tauopathies such as Alzheimer’s disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau’s pathological changes are closely linked to neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau’s physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament’s ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.

Type: Article
Title: Quantitative live cell imaging of a tauopathy model enables the identification of a polypharmacological drug candidate that restores physiological microtubule interaction
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41467-024-45851-6
Publisher version: http://dx.doi.org/10.1038/s41467-024-45851-6
Language: English
Additional information: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > VP: Health
UCL > Provost and Vice Provost Offices > VP: Health > Translational Research Office
URI: https://discovery.ucl.ac.uk/id/eprint/10188241
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