Elucidating the Effects of Post-Translational Modifications on Tau Binding to F-actin and PSD95

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Project Summary/Abstract Alzheimer’s disease (AD) and other tau-related neurodegenerative diseases are characterized by neurofibrillary tangles which are composed of aggregates of the microtubule associated protein tau. The accumulation of these tangles contributes to neuronal death and cognitive decline. While millions nationally are plagued by Alzheimer’s, therapeutic efforts focusing on one of the main hallmarks of the disease, amyloid-beta (Aβ) plaques, have remained unsuccessful. The lack of correlation between treatment and robust cognitive improvement during these clinical trials highlight the urgent need to elucidate the preclinical mechanistic changes driving disease manifestation. The physiological roles of tau include the stabilization of microtubules, and bundling of F-actin filaments. While tau-microtubule interactions are well-studied, tau interactions with F- actin are more poorly understood, but are reported to drive the development of pathological species such as Hirano bodies, actin inclusions found in AD brains and other tauopathies. Tau can form other functional or pathological interactions, including recently reported binding to post-synaptic density protein 95 (PSD-95), which was shown to interfere with functional hyperemia and promote the neurotoxicity induced by amyloid- beta. Tau is also modified by a rich array of post-translational modifications (PTMs), which have been shown to alter normal and pathological tau interactions. This proposal will test the central hypothesis that tau PTMs within the critical PHF6 and PHF6* hexapeptide motifs modulate tau interactions with binding partners such as PSD-95 and F-actin and thereby contribute to the role of these partners, as well of changes in tau structure and function, in specific processes associated with disease manifestation. Using biophysical methods, including nuclear magnetic resonance (NMR) spectroscopy, I will characterize the interactions of tau with F-actin and PSD-95 and assess the effects of PTMs located within the PHF6 and PHF6* motifs on these interactions. Our structural observations, complemented by functional studies performed both by myself and our collaborators, will contribute to a deeper understanding of the mechanistic changes in tau behavior that drive the manifestation of AD and other tauopathies, and facilitate the development of novel therapeutic targets for the treatment of tau-based neurodegeneration.