Structural profiling of tauopathy seeds

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PROJECT SUMMARY/ABSTRACT Alzheimer’s disease and other tauopathies are tau protein conformation diseases that impact millions of people. There is currently no means to diagnose patients based on tau conformation. The microtubule associated protein tau can convert into distinct pathogenic shapes each causing different human diseases. High-resolution cryo- Electron Microscopy structures of tau fibrils isolated from different diseases reveal the diversity of structures that tau can adopt in each disease. Fibril structures highlight the central role of amyloidogenic motifs forming stabilizing nonpolar contacts to determine the distinct folds. Our model predicts that the propensity of a tau monomer to adopt structural polymorphs is linked to perturbation of local structures that expose different patterns of amyloidogenic motifs. Detection of tauopathy-derived tau conformations will be essential to develop accurate disease diagnoses. To understand the structure and origins of tau amyloid assembly in tauopathies, we propose to: (i) develop predictive algorithms for tau structure based on functional genetics, (ii) test role of local motifs in control of tau assembly, (iii) test role of pathogenic mutations on local structure. We anticipate that our approach will allow diagnosis of tauopathies based on tau conformation in premortem, and possibly presymptomatic, patients samples, and also provide fundamental insight into the rules that govern tau assembly in disease. Our long-term goal is to develop diagnostic and therapeutic approaches to treat neurodegenerative diseases. This project is in alignment with the mission of the NIA to support biological and clinical research on aging.