Tennant, William
(2024)
TDP-43 Phosphorylation State Regulates Solubility, Localization, and Cellular Toxicity.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The hyperphosphorylated and insoluble TDP-43 inclusions are a pathological hallmark of several neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), frontal temporal dementia (FTD), and Alzheimer's Disease (AD). The mechanism by which phosphorylation regulates TDP-43 physiological functions and its contribution to the observed neuropathology remain unclear. To assess this, we generated recombinant TDP-43 proteins that mimic the hyperphosphorylated and hypophosphorylated condition to study the effect of TDP-43 phosphorylation of the LCD on phase separation, cellular localization, and cytotoxicity. Our studies show that both hyper- and hypo- phosphorylation mimetics promote TDP-43 mislocalization to the cytoplasm , enhance the propensity and stability of the TDP-43 C-terminal domain protein droplets, and disrupt phase separation. However, in all models it is only the phosphodeficient condition that reduces TDP-43 solubility and promotes the formation of cytotoxic aggregates. Furthermore, phosphodeficient TDP-43 induces the sequestration of endogenous TDP-43 to these insoluble aggregates that ultimately diminish TDP-43 splicing capacity. Taken together, our efforts provide further evidence that insoluble, cytoplasmic TDP-43 inclusions are cytotoxic and that phosphorylation might actually play a protective role, inhibiting the formation of insoluble, toxic, cytoplasmic TDP-43 aggregates.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
16 September 2024 |
| Date Type: |
Publication |
| Defense Date: |
9 February 2024 |
| Approval Date: |
16 September 2024 |
| Submission Date: |
4 April 2024 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
108 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
ALS, TDP-43, Phosphorylation, Liquid-liquid phase separation, neurodegenerative disease, RNA binding proteins, post-translational modifications |
| Date Deposited: |
16 Sep 2024 19:09 |
| Last Modified: |
16 Sep 2025 12:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46014 |
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