Do Post-Translational Modifications Cause Tau to Shapeshift?

We aim to identify the post-translational modifications on tau that promote its misfolding into the specific aggregate structures we observe in Alzheimer’s Disease.

We will generate a library of hundreds of tau variants mimicking post-translational modifications. We will use a high throughput biochemical platform to analyze aggregates for each tau variant, directly comparing their structural properties. We aim to identify tau variants that recreate aggregate structures observed in Alzheimer’s Disease and capitalize on the discovery of alternate aggregate structures to gain insight regarding what makes a structure harmless versus toxic. Thus, we will test the ability of tau variants with different aggregate structures to promote pathology in mice.

Our innovation was to create a high-throughput, small-scale platform to perform direct cross comparisons of tau aggregate structures in vitro. It is this innovation that allows us to study the potential modulatory effects of hundreds and potentially thousands of factors at a time. In this proposal we focus on post-translational modifications (PTMs) as potential modulatory factors. However, our methodology is designed to be readily adaptable to study other factors linked to tau aggregation.

Our study aims to greatly enhance our fundamental knowledge of how PTMs on tau directly influence the aggregate structures produced. By studying hundreds of individual tau variants, we predict we will be able to identify key sequence elements or regions of tau that lead to the formation of one tau aggregate structure versus another. This data will form a strong foundation for future biophysical and biochemical studies dissecting the molecular details underlying tau misfolding pathways and how they can be targeted early and effectively.