Thesis
Tip60 nucleocytoplasmic transport to elucidate its role in neuronal function
Master of Science (M.S.), Drexel University
Mar 2025
DOI:
https://doi.org/10.17918/00010889
Abstract
Histone acetylation is a key regulatory mechanism in neuroepigenetic homeostasis, essential for proper gene expression and neurological function. This balance is mediated by the interplay between histone acetyltransferases (HATs) and histone deacetylases (HDACs). Tip60 HAT, a multifunctional HAT, has been implicated in both cancer and neurodegenerative diseases, where its nuclear and cytoplasmic mislocalization is observed, suggesting the importance of proper Tip60 nucleocytoplasmic transport (NCT). We previously demonstrated that in a well-characterized Alzheimer's Disease (AD)-associated APP Drosophila model, Tip60 HAT exhibits increased cytoplasmic localization relative to the nucleus, associated with developmental defects, early lethality, and locomotive dysfunction. Yet, the potential impact of Tip60 nuclear accumulation in the Drosophila brain remains unclear. Our lab previously identified a novel nuclear export signal (NES) sequence in the Drosophila Tip60 sequence, which is highly conserved to the mammalian Tip60 sequence. To investigate its functional significance, we generated a transgenic Drosophila line carrying a mutated NES and employed this model in this study to test the hypothesis that disruption of Tip60 NCT negatively affects Drosophila development and neuronal function. Using various behavioral assays, we demonstrated that mutating the NES sequence does not induce early developmental defects but shows compromised longevity. Conversely, Tip60 overexpression promotes lifespan, highlighting the essential function of Tip60 NCT. Additionally, we observed enhanced locomotor performance in both NES mutant and Tip60 overexpression fly lines, potentially linked to the positive synaptic marker changes. Our results establish that Tip60 nuclear accumulation increases locomotion, but proper Tip60 NCT is important for longevity, highlighting the importance of proper Tip60 HAT transportation and subcellular localization for normal development and neuronal functions, which may be disrupted in AD.
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Details
- Title
- Tip60 nucleocytoplasmic transport to elucidate its role in neuronal function
- Creators
- Huong Anh Mai
- Contributors
- Felice Elefant (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Master of Science (M.S.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 64 pages
- Resource Type
- Thesis
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 991022040863404721