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Dissertation
An epigenetic role for tip60 in APP mediated neuronal processes
Doctor of Philosophy (Ph.D.), Drexel University
Jan 2013
DOI:
https://doi.org/10.17918/etd-6049
Abstract
Dynamic epigenetic regulation of neurons is emerging as a fundamental mechanism by which neurons adapt their transcriptional responses to specific developmental and environmental cues. Recent studies bolster the concept that age associated aberrant changes to the epigenetic modification code within the genome of the brain, specifically histone acetylation, cause gene misregulation that drive cognitive decline. Tip60 is a histone acetyltransferase (HATs) enzyme that is involved in the transcriptional regulation of genes enriched for neuronal function and control of synaptic plasticity. Accordingly, Tip60 has been implicated in the neurodegenerative disorder Alzheimer's disease (AD) via transcriptional regulatory complex formation with the AD linked amyloid precursor protein (APP) intracellular domain (AICD). As such, misregulation of neuronal target genes by the Tip60/AICD complex is thought to lead to neurotoxicity associated with AD. However, a direct and causative epigenetic based role for Tip60 HAT activity in mediating such gene expression changes in vivo remains unclear and is thus the subject of this study. Chapter 1 reviews the role of specific HATs including Tip60 in mediating neuronal survival and high order brain functions like learning and memory. The pros and cons of using HDACi as therapeutic strategies and the beneficial effects of modulating the function of specific HATs in neurodegenerative diseases is also discussed. Chapter 2 demonstrates a functional interaction between Tip60 and APP during neurogenesis using a transgenic AD fly model that was uniquely adapted to induce varying levels of Tip60 HAT activity and describes the neuroprotective role Tip60 HAT activity exhibits towards AD neurodegenerative pathology. Chapter 3 demonstrates that Tip60 HAT activity in conjunction with APP mediates axonal growth of the Drosophila pacemaker cells, the sLNvs, and their production of the neuropeptide PDF to stabilize Drosophila sleep-wake cycles. The study provides novel insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like AD. Chapter 4 describes the effects Tip60 plays in mediating gene expression changes that underlie memory formation in Drosophila via the mushroom body encompassing neural circuit. Together, these studies add dTip60 to the growing list of HAT chromatin regulators critical for nervous system function.
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Details
- Title
- An epigenetic role for tip60 in APP mediated neuronal processes
- Creators
- Sheila K. Pirooznia - DU
- Contributors
- Felice Elefant (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biology; College of Arts and Sciences; Drexel University
- Other Identifier
- 6049; 991014632417004721