Tau neurofibrillary tangle (NFT) deposits are a characteristic hallmark of Alzheimer's disease and their appearance correlates closely with cognitive decline and disease progression. Mutations in tau cause frontotemporal dementia, establishing a critical role for tau in the etiology of neurodegeneration and dementia. In Alzheimer's disease, tau becomes hyperphosphorylated, likely leading to its release from microtubules and thereby facilitating its subsequent assembly into pathological aggregates. Other tau post-translational modifications (PTMs) such as acetylation are also implicated in disrupting tau-microtubule interactions and promoting tau aggregation. However, considerable evidence suggests that mature tau fibrils found in NFTs are not the species that cause neuronal death, and instead that oligomeric intermediates formed during the conversion of tau from a monomer to a highly ordered fibril are the toxic species. While recent breakthroughs have provided high-resolution structures of brain-derived tau aggregates, the structures of tau oligomers remain largely unknown.
In aim 1 of this proposal, we will determine the structure of a novel membrane- induced toxic tau oligomer that we recently discovered using a combination of cutting edge solid-state NMR and ESR spectroscopy. By generating the first detailed structure picture of any toxic tau oligomeric species, we will advance our understanding of the interactions that stabilize tau oligomers and make possible structure function studies of their formation and their toxicity. The details of how PTMs influence tau interactions with microtubules or other interaction partners remain poorly understood. Recently, our collaborators discovered a novel tau PTM, lysine-succinylation, which occurs specifically in Alzheimer's brains but not in control brains and promotes tau aggregation, suggesting that it may contribute to disease development.
In aim 2 of this proposal, we will determine the effects of this novel PTM on the functional interactions of tau with microtubules, as well as with unassembled tubulin and cell membranes. We will compare these effects to those of lysine-acetylation, which has been shown to be a key mediator of tau function and toxicity. We will employ a combination of direct and saturation transfer NMR methods using tau peptides, tau fragments and full-length tau isoforms. Our in vitro measurements will be correlated with and will inform studies on how these PTMs affect tau interactions in model cells and cultured neurons. The results may provide alternative functional tau targets for disease intervention, important given the challenges associated with targeting amyloid aggregates and aggregation cascades. In addition to perturbing functional interactions of tau, PTMs may also directly influence the formation and structure of tau aggregates.
In aim 3 of this proposal, we will investigate the effects of lysine-succinylation and acetylation on membrane-induced tau oligomer formation, structure and toxicity. Given the potential role of existing and novel tau PTMs in disease, this information may be useful for the development of novel tau-targeted therapeutics.
Oligomers of the protein tau are thought to be key contributors to the death of brain cells in Alzheimer's disease, but we don't know their structures. Here we propose to determine, for the first time, the structure of a toxic oligomeric form of tau. Because tau function, aggregation and toxicity are modulated by covalent modifications, we also aim to clarify how such modifications influence tau function and tau oligomers.
