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Building an Atlas of Tau Phosphorylation Sites Involved in Synaptic Plasticity and Disease
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Building an Atlas of Tau Phosphorylation Sites Involved in Synaptic Plasticity and Disease
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Dissertation
Building an Atlas of Tau Phosphorylation Sites Involved in Synaptic Plasticity and Disease
2022
Overview
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by amyloid beta (Ab) and neurofibrillary tangles (NFTs) containing the microtubule associated protein tau. Tau pathology is highly correlated to neuronal loss, unlike plaque load. Tau likely acts as a downstream effector of Ab, leading to neurotoxicity. Indeed, the loss of tau can rescue neurotoxicity. Furthermore, aggregated tau propagates in a prion-like manner, initiating a toxic cascade. It has been shown that its release is exacerbated via excitation. Thus, tau-directed approaches for novel treatments of AD are essential. The hyperphosphorylation of tau is seen in all tauopathies, not exclusively AD, suggesting an essential role in pathogenesis. Physiologically, tau is unfolded, suggesting that aggregated, phosphorylated tau is pathological. To understand neurodegenerative pathways, it is imperative to study the pattern of tau phosphorylation. However, there are over 80 potential phosphorylation sites on tau resulting in an ambiguous definition of “phosphorylated tau”. We are particularly interested in tau’s role in hyperexcitation because aberrant overactivity is a characteristic of AD as well as other tauopathies and may be via catalyst for further pathogenesis. Here, we used unbiased mass spectrometry(MS) to perform comprehensive mapping of tau phosphorylation patterns during hyperexcitation. We have identified a unique signature of tau phosphorylation during hyperexcitation S409, S412, S413, T414, S416, S422,and T427. Subsequently, we mutated each of these to phosphor-mimetic or phosphor-null sites to identify any changes associated with tau localization, neuronal morphology, and spine morphology. We found that individual sites display different phenotypes of tau, effecting tau intensity at particular subcellular locations and neuronal branching. Lastly, we identified the phosphorylation patterns over time in various mouse models. We found overtime tau phosphorylation patterns differ between sex and age. These results will begin to decipher the phosphorylation code that governs tau function in physiology and pathology. Defining the phosphorylation profile of tau is highly significant for understanding basic mechanisms involved in hyperexcitation and disease progression in neurodegeneration. This work will help guide new therapeutic approaches for targeting pathogenic tau in tauopathies such as AD.
