Tauopathies, a heterogeneous group of neurodegenerative diseases, feature insoluble deposits of the microtubule-associated protein tau. A causal role for tau misfolding in disease is supported by the fact that multiple mutations associated with an increased propensity for aggregation cause autosomally dominant forms of the disease. Previous work from our lab as well as from others'suggests that the tau protein can propagate misfolding from the outside to the inside of the cell, and between cells in a prion-like fashion. This mechanistic paradigm is also implicated in other disorders including synucleinopathies, polyglutamine expansion diseases, and frontotemporal dementia/ALS spectrum diseases. However, whether or not the proteins associated with these diverse diseases are true prions, defined by the ability to propagate unique conformations, is an unsettled matter. Preliminary data suggests that exogenous tau fibrils induce the misfolding of endogenously expressed tau repeat domain (RD, aa 244-372), which stably propagates its amyloid state to daughter cells as biochemically distinct prion strains. These conformations can be isolated from cells and re-introduced into na?ve cells to seed self-propagating aggregates with the same phenotypic characteristics. Brain homogenates from human patients with different tauopathies induce the formation of unique tau aggregate strains. Building on preliminary data, the present work addresses two hypotheses: 1) Distinct strains are associated with distinct tauopathies;2) There is a direct correlation between a strain's conformational stability and its ability to seed further aggregation and induce toxicity. If successful, this work will provide compelling evidence for tauopathies having a prion etiology and will gather mechanistic insight into the factors that dictate strain formation, strength, and toxicity. This research is significan because it could help lead to more accurate diagnosis of tauopathies, and to more precise antibody-based treatments that target extracellular protein, which are gaining increasing attention as potential therapies

Public Health Relevance

Currently, therapeutics that slow the progression of Alzheimer's disease and other tauopathies are nonexistent. The proposed research aims to examine the hypothesis that distinct tau prion conformations/strains are associated with individual tauopathies. If demonstrated, this has implications for the design of targeted therapies that prevent propagation of disease throughout the nervous system.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Sanders, David W; Kaufman, Sarah K; Holmes, Brandon B et al. (2016) Prions and Protein Assemblies that Convey Biological Information in Health and Disease. Neuron 89:433-48
Kaufman, Sarah K; Sanders, David W; Thomas, Talitha L et al. (2016) Tau Prion Strains Dictate Patterns of Cell Pathology, Progression Rate, and Regional Vulnerability In Vivo. Neuron 92:796-812
Mirbaha, Hilda; Holmes, Brandon B; Sanders, David W et al. (2015) Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. J Biol Chem 290:14893-903
Sanders, David W; Kaufman, Sarah K; DeVos, Sarah L et al. (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271-88