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ORCID
https://orcid.org/
0009-0000-7276-6302
Access Type
Campus-Only Access for Five (5) Years
Document Type
thesis
Embargo Period
1-28-2024
Degree Program
Molecular & Cellular Biology
Degree Type
Master of Science (M.S.)
Year Degree Awarded
2024
Month Degree Awarded
February
Abstract
Microtubule Associated Protein Tau (Tau) is found intracellularly along the axons of neurons in the central nervous system where they stabilize the microtubules by binding along its lattice. In disease, Tau becomes hyperphosphorylated, dissociates from the microtubule, oligomerizes, and eventually forms neurofibrillary tangles (NFT). These NFTs then spread in a prion-like manner starting from the entorhinal cortex to the frontal lobe, as it does in Alzheimer’s Disease (AD). AD is the most common form of dementia, characterized by the decline of cognition and function. Since the 1980’s the field has shown that post-mortem brains of AD patients have ‘hyperphosphorylated’ Tau tangles and the working model suggests that hyperphosphorylation is the cause for dissociation and thus aggregation. However, the definition of hyperphosphorylated Tau remains ambiguous. Previous findings show specific sites of Tau modification being significant in disease. Mass spectrometric data further corroborates these findings by indicating specific sites of phosphorylation with high frequency and extent modification, including epitopes AT100 (T212, S214, T217), 12E8 (T262, S263), and PHF1 (S396, S400, T403, S404). In this study, I aim to show that the term ‘hyperphosphorylation’ is misleading as it is truly the aberrant phosphorylation of Tau at specific sites that increase aggregation propensity in disease. I will do this by studying co-factor free aggregation kinetics using a Thioflavin T probe with different Tau constructs modified at specific sites of interest. These results will provide a new perspective into the Tau hypothesis of AD and serve to update AD therapeutics.
First Advisor
Dr. Jennifer Rauch
Second Advisor
Dr. Margaret Stratton
Third Advisor
Dr. Peter Chien
Creative Commons License
This work is licensed under a Creative Commons Attribution-Share Alike 4.0 License.
Recommended Citation
Sebastian, Navya T., "UNDERSTANDING THE FUNCTIONAL IMPACT OF DISEASE-ASSOCIATED PHOSPHORYLATION SITES ON THE NEURODEGENERATIVE PROTEIN TAU" (2024). Masters Theses. 1417.
https://scholarworks.umass.edu/masters_theses_2/1417