Tau-seed protein interactome and its role in neurodegenerative tauopathies

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Pathological aggregation of tau and the preponderance of neurofibrillary tangles (NFT) or other inclusions containing tau are defining histopathological features of Alzheimer's disease (AD) and many neurodegenerative diseases collectively known as tauopathies. A major focus of research has been the understanding of the propagation of pathological tau in AD patient brains that follow neuronal networks. Despite the knowledge acquired, the cellular mechanism involved in tau propagation, the nature of the tau species involved in the spreading and the precise seeding/template remains unclear. Considering the preponderant role of tau propagation in the pathogenesis of AD and other tauopathies, we performed an unbiased quantitative Mass Spectrometry based study to determine the specific tau species involved in the spreading and the proteins that specifically interact with this “tau-seed”. Bassoon (BSN), a large scaffolding protein of the presynaptic active zone, was identified as a significant interactor of the tau-pathological-seed isolated from a mouse model for tauopathy, as well as from AD and PSP postmortem samples. Prior research in AD and PSP patient samples have linked BSN with both tauopathies. Therefore, the main goal of this proposal is to determine and dissect the mechanism by which BSN functions as a scaffold to stabilize and facilitate the spreading and neurotoxicity of a tau-pathological-seed. By introducing a series of biochemical, molecular, histological, electrophysiological, behavioral, imaging, bioinformatics and Mass Spectrometry based strategies together with mouse model, cellular culture and human postmortem tissue, this proposal will 1. evaluate the role of BSN in tau pathogenesis in vivo, 2. determine the mechanistic base of BSN in tau aggregation, propagation and synaptotoxicity in neuronal systems and 3. test if BSN's association with tau-pathological-seed is strain specific in human brains from a diverse set of tauopathies. Gaining a better understanding of the contribution of BSN on the formation, stabilization and propagation of a pathological tau-seed is highly significant since it may provide important information that will increase our understanding on the mechanism(s) involved in tau propagation, the precise nature of the tau-seed involved in this process and its role in the neurodegeneration associated to AD and other tauopathies.