The Structural Basis of Protein Pathology in Tauopathy

Neurodegenerative diseases such as Alzheimer’s are based on accumulation of the tau protein and have myriad presentations. It is critical to understand the basis of this variability to achieve precise diagnosis and treatment, but current methods of neuropathology are not adequate to explain why patients experience different types of disease. Tau has many characteristics similar to the prion protein, including the formation of distinct, highly ordered assemblies (also termed “strains”) that have unique 3D structures, determining the nature of pathology they cause in the brain. This project combines structural biology, biochemistry, and neuropathology in an attempt to precisely link novel tau structures with specific diseases. It will develop new tools to analyze tau from human brain tissues, with the goal of achieving more precise diagnosis based on quantitative measures. This could enable more personalized approaches to the diagnosis and treatment of neurodegenerative diseases.

The Joachimiak lab defined how local domains in tau fold into distinct fibril conformations (strains) linked to disease, and how molecular chaperones control tau at different steps of the folding pathway. The White lab provided deeply phenotyped human autopsy brain tissue from subjects with multiple tauopathies for tau seed and strain analyses by the Diamond lab and for biophysical studies of tau by the Joachimiak lab. The White lab also created digital whole slide images from immunostained tissue sections for analysis using machine learning to discover new patterns of disease pathology not evident to the human eye. The Diamond lab developed and characterized conformation-specific tau antibodies in collaboration with the Joachimiak and White labs, and refined biosensor cell lines to discriminate different tauopathies.