Methods for high throughput discovery of fluoroprobes that recognize tau fibril polymorphs.

Autor:	Carroll EC; Department of Chemistry, San José State University, San José, CA 95192.; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Yang H; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158.; Department of Pharmaceutical Chemistry, University of California San Francisco; San Francisco, CA 94158., Jones JG; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Oehler A; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Charvat AF; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Montgomery KM; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Yung A; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158., Millbern Z; Department of Textile Engineering, Chemistry and Science, North Carolina State University, Raleigh, NC 27695., Vinueza NR; Department of Textile Engineering, Chemistry and Science, North Carolina State University, Raleigh, NC 27695., DeGrado WF; Department of Pharmaceutical Chemistry, University of California San Francisco; San Francisco, CA 94158., Mordes DA; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158.; Department of Pathology, University of California San Francisco; San Francisco, CA 94158., Condello C; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158.; Department of Neurology, University of California San Francisco; San Francisco, CA 94158., Gestwicki JE; Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158.; Department of Pharmaceutical Chemistry, University of California San Francisco; San Francisco, CA 94158.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Sep 02. Date of Electronic Publication: 2024 Sep 02.
DOI:	10.1101/2024.09.02.610853
Abstrakt:	Aggregation of microtubule-associated protein tau (MAPT/tau) into conformationally distinct fibrils underpins neurodegenerative tauopathies. Fluorescent probes (fluoroprobes), such as thioflavin T (ThT), have been essential tools for studying tau aggregation; however, most of them do not discriminate between amyloid fibril conformations (polymorphs). This gap is due, in part, to a lack of high-throughput methods for screening large, diverse chemical collections. Here, we leverage advances in protein adaptive differential scanning fluorimetry (paDSF) to screen the Aurora collection of 300+ fluorescent dyes against multiple synthetic tau fibril polymorphs. This screen, coupled with orthogonal secondary assays, revealed pan-fibril binding chemotypes, as well as fluoroprobes selective for subsets of fibrils. One fluoroprobe recognized tau pathology in ex vivo brain slices from Alzheimer's disease patients. We propose that these scaffolds represent entry points for development of selective fibril ligands and, more broadly, that high throughput, fluorescence-based dye screening is a platform for their discovery. Competing Interests: Competing Interests The authors have no competing interests to disclose.
Databáze:	MEDLINE
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