In Alzheimer?s Disease and other dementias, the microtubule associated protein tau forms neurofibrillary tangles, that leads to neuronal cell death and cognitive decline. Although Alzheimer?s Disease currently affects over 5 million people in the united states, the molecular interactions that drive the onset and spread of the disease remain poorly understood. Normally tau?s function is to bind to microtubules, aid in their assembly and disassembly, and in turn provide stability for essential intra-neuronal transport. Disruption of tau?s binding to microtubules by post translational modifications (PTMs) can drive tau?s abnormal structure and function, becoming toxic to the neuron by manifesting itself first as small oligomers and later as paired helical filaments. Although tau neurofibrillary tangles have remained a key pathological identifier of AD, recent evidence suggests smaller tau oligomers may play a toxic role in disease. This project will test the hypothesis that specific novel structural features of tau underlie its interactions with microtubules and lipid membranes at important sites of activity, that these structural features can be affected by PTMs, and that such changes can modulate tau?s ability to oligomerize and thereby modulate toxicity. The project addresses a novel tau PTM, succinylation; oligomer structure of novel membrane-induced tau oligomers; and the role of PTMs on oligomer structure and toxicity. Biochemical methods, spectroscopic techniques, nuclear magnetic resonance, and electron microscopy will be used to 1) characterize structural features of tau and PTM tau when interacting with physiological binding partners (lipids and microtubules) and 2) characterize the structure of tau and PTM tau oligomers. Structural studies will be done in parallel with neuronal assays to understand how PTMs affect oligomeric tau toxicity. The proposed research includes an extensive training plan that encompasses academic and scientific support for the success of the fellow in the fields of fundamental biophysics, biochemistry, neuroscience, and structural biology. All of the proposed research and fellowship training will take place in the interdisciplinary environment available at Weill Cornell Medicine. While the project seeks to improve current methods used to study the structure of other highly dynamic proteins and other oligomers, it offers an opportunity to gain a deeper understanding of the function of a protein that is critically important in human disease.
Alzheimer?s Disease is an extremely prevalent disease in the United States that has no effective treatment. This proposal aims to use biophysical, biochemical, and structural biology techniques to test a unique hypothesis that will contribute to fundamental knowledge on novel structure-function relationships of the protein tau by studying the effects of post translational modifications on tau physiological interactions, oligomer structure, and oligomer toxicity in neurons. In the long term, our research should facilitate the development of novel therapeutic strategies for treatment and prevention of Alzheimer?s Disease.
