Tau Strains

Prions exhibit distinct “strains,” which are conformers that replicate faithfully in serial transmission between hosts, and produce predictable patterns of neuropathology. We previously determined that tau forms strains in cells and mice.

We have created stable cell lines that indefinitely and faithfully propagate unique tau prion strains from mother to daughter cells. When a tau prion is purified from one cell and introduced into a naïve cell, this recreates the same strain, proving that the tau amyloid structure itself encodes all the information required to establish unique patterns of disease biology.

Indeed, when we introduce a tau prion strain isolated from a cell into a vulnerable animal, it produces strain-specific neuropathology that can be passaged between animals, and even back into the cultured cell system. Each strain produces a distinct and predictable pattern of neuropathology after inoculation into a mouse brain.

Recent advances in cryogenic electron microscopy (cryoEM), which has revealed atomic-level detail about some tau structures, have confirmed our original conclusions about tau’s diverse structures, and raised new questions.

We have recently exploited functional genetics to rapidly classify tau structures for the purposes of better diagnosis, and understanding the triggers that lead certain strains to form. This is based by sequential introduction into tau of alanine substitutions, which differentially affect the ability of the protein to incorporate into unique strains. By identifying residues required to form each strain’s “core,” these methods have confirmed the essential prion properties of tau, and allowed us to “fingerprint” tau strains to precisely identify them. This is transforming our ability to study their formation, and to develop agents that target them for diagnosis and therapy.