Small molecule tools for molecular recognition of tau fibril conformations.

Abstract

Aggregation of the protein tau into filamentous inclusions (fibrils) underlies the devastating neurodegenerative diseases known as tauopathies. Recent advances in structural biology have revealed that tau fibrils adopt unique tauopathy-dependent conformations in patient brains that differ from those of heparin-induced recombinant tau fibrils in vitro. However, a mechanistic understanding of how these disease-specific conformations arise is hampered by the lack of rapid biochemical tools for molecular recognition of tau fibril conformations. Here, we develop a library of polyanionic inducers of tau aggregation to create conformationally diverse tau fibril forms in vitro and in seeded cell culture. We leverage this ability to generate different fibril conformations to screen a library of fluorogenic chemical probes for the ability to differentiate between fibril forms. From this screen, we identify fluoroprobes that recognize distinct fibril conformations and may serve as accessible tools for dissecting molecular mechanisms driving tau aggregation. We envision that this toolkit can be used for systematic characterization of how a cellular factor of interest modulates tau's conformational landscape to induce disease-associated fibril conformations.