Toward a Molecular Understanding of Tau-Mediated Neurodegeneration
A common feature of more than 20 neurodegenerative diseases, including Alzheimer's disease, frontotemporal dementia, and progressive supranuclear palsy, is the accumulation of pathological, amyloid-like aggregates of the protein tau. The formation of these aggregates is a multi-step process that starts from unfolded individual tau molecules, progresses through intermediates containing several copies of tau, and ends in highly ordered, elongated, and unbranched filaments. Molecular dissection and structural characterization of this pathway has encountered great difficulties because of the size and complexity of the involved aggregates. High-resolution methods such as X-ray crystallography and solution NMR spectroscopy that have proved unwaveringly successful in revealing the structures of soluble proteins have, until now, encountered insurmountable technical challenges.
We have sought alternative strategies to obtain structural information on the different forms of tau in the aggregation process. One strategy that has proved very successful is the labeling of tau with a small reporter molecule that allows us to follow the structural changes using a technique called electron paramagnetic resonance spectroscopy. This method faithfully delivers structural detail regardless of the size and shape of the investigated species. Using this novel approach in combination with other biophysical techniques, we have gained first insights into the fine structure of tau filaments. A major goal of our lab is to extend these investigations in order to obtain a complete three-dimensional model of the tau filament. Similarly, we are analyzing the structures of tau intermediates and tau monomers and are assessing the effects individual species have on cell viability. A molecular understanding of the folding properties of tau and its cellular interactions and structural transitions along the path from the single subunit to the complex filament will be an important prerequisite for the design of new drugs that intervene in the assembly process.