Dissertations, Theses, and Capstone Projects

Date of Degree

2-2026

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy

Program

Biology

Advisor

Alejandra Alonso

Committee Members

Abdeslem El-Idrissi

Greg Phillips

Frida Kleiman

Sara Guariglia

Viktoriya Morozova

Subject Categories

Biochemistry | Molecular and Cellular Neuroscience | Nervous System Diseases

Keywords

Alzheimer's disease, tau, oxidative stress, nucleocytoplasmic transport

Abstract

Tau is traditionally associated with the cytoskeleton but is gaining recognition as a bona-fide nuclear protein. However, the role of nuclear tau in tauopathies is unclear. Our lab has previously generated a pathological form of tau pseudophosphorylated at S199, T212, T231, and S262 (PH-tau) that mimics the pathological behavior of AD-tau. PH-tau is shown to translocate into the nucleus of transiently transfected HEK-293 cells, whereas wildtype tau does not. Disruption of a putative NLS in the tau sequence prevents tau from entering the nucleus. The nuclear translocation of PH-tau requires both importin-α and importin-β. Nuclear PH-tau triggered a large increase in cell death, but this could be entirely prevented by blocking its entry into the nucleus. PH-tau-expressing cells also exhibited disruption of the nuclear lamina and mislocalization of TDP-43 and Ran to the cytoplasm. PH-tau does not bundle microtubules, and this effect is independent of nuclear translocation. These results demonstrate that the mechanism of tau translocation into the nucleus involves importin-α/β, and that PH-tau exhibits toxicity after its nuclear translocation. This suggests a model where hyperphosphorylated tau not only disrupts the microtubule network, but also translocates into the nucleus, inducing mislocalization of nuclear proteins and, ultimately, causing cell death.

Tau has a known relationship with oxidative stress, which has long been recognized as a contributor to AD pathogenesis. Despite this, we still do not have a complete understanding of how oxidative stress influences the development of tauopathies, particularly on a more chronic timeframe. I report that acute and chronic oxidative stress conditions lead to different subcellular distributions of tau, with acute stress promoting nuclear translocation and chronic stress returning some nuclear tau to the cytoplasm. Both stress conditions increase tau phosphorylation at T212, T231, and S262. Tau phosphorylation at T212 is greater in the cytosol, while tau phosphorylation at T231 is greater in the nucleus. However, tau phosphorylated at S262 is found only in the nucleus, suggesting a key role for this site in regulating tau shuttling. Stress conditions triggered an increase in cell death, which was attenuated by the expression of either WT-tau or tau-R406W. The protective effect of these tau forms was notably stronger under chronic stress. PH-tau expression further increases the toxicity caused by acute stress and triggers cell death even in non-tau-expressing cells. Both of these effects are reduced under chronic stress conditions. An increase in tau aggregation is also observed for both acute and chronic stress, but the effect of chronic stress is more pronounced. From these results, I propose that tau acts as a stress-response protein under both acute and chronic stress conditions, but through different mechanisms, with the acute stress response relying on tau’s DNA-binding capability, and the chronic stress response relying on its aggregation.

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