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Dissertation
Tip60 and HDAC2 epigenetic mechanisms are critical for neuronal health and are disrupted in the neurodegenerative brain
Doctor of Philosophy (Ph.D.), Drexel University
May 2021
DOI:
https://doi.org/10.17918/00000823
Abstract
Epigenetic mechanisms, specifically the balance between histone modulators histone acetyltransferases (HATs) and histone deacetylases (HDACs) are important to neuronal function from early cell type determination stages of development to creation and maintenance of synapses responsible for neuronal communication and output. This balance between HATs and HDACs like Tip60 HAT and HDAC2, is dynamic and susceptible to disproportion. In a scenario with consistent imbalance between Tip60 and HDAC2, we observe neuronal dysfunction in the form of improper histone acetylation and gene expression, decline in cognition, changes in synapses, disruptions in Tip60 and HDAC2 binding to target genes, and resulting neuronal death. We observe epigenetic imbalance linked to neuronal function in multiple neurodegenerative diseases including Alzheimer's Disease (AD), Huntington's Disease (HD), Parkinson's Disease (PD) and Amyotrophic Lateral Sclerosis (ALS). While each disease has unique associated symptoms and seemingly unique versions of epigenetic dysfunction, the common factors between all four diseases link them as neurodegenerative disorders that with an untreated early onset of epigenetic imbalance it leads to increased severity of neurodegenerative phenotypes. Astounding outcomes discovered by work completed in our lab showed that increasing Tip60 is able to entirely rescue to begin to restore side effects seen in each of the four diseases. This accumulation of work leads us to a concept where identification of early disruptions can be critical for treating neurodegenerative disease and one of these early disruptions that may be a fruitful biomarker for early diagnostics is the decrease in HATs such as Tip60 and the increase in HDACs such as HDAC2. In conjunction with that, increasing HAT levels in neurodegenerative disease leads to improved outcomes and has less severe side effects than decreasing HDAC activity suggesting that it is beneficial to target HATs as a therapeutic for these diseases.
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Details
- Title
- Tip60 and HDAC2 epigenetic mechanisms are critical for neuronal health and are disrupted in the neurodegenerative brain
- Creators
- Mariah Beaver
- Contributors
- Felice Elefant (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- 148 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 991015241980104721