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Dissertation
Characterizing G-quadruplex Mediated Regulation of Amyloid Precursor Protein Expression
Doctor of Philosophy (Ph.D.), Drexel University
Oct 2016
DOI:
https://doi.org/10.17918/etd-7245
Abstract
A central event in Alzheimer's disease is the accumulation of amyloid [beta] (A[beta]) peptides generated by the proteolytic cleavage of the amyloid precursor protein (APP). APP overexpression leads to increased A[beta] generation and Alzheimer's disease in humans and altered neuronal migration and increased long term depression in mice. Conversely, reduction of APP expression results in a decreased A[beta] levels in mice as well as impaired learning and memory and decreased numbers of dendritic spines. Together these findings indicate that therapeutic interventions that aim to restore APP and A[beta] levels must do so within an ideal range. To better understand the effects of modulating APP levels, we explored the mechanisms regulating APP expression focusing on post-transcriptional regulation. Such regulation can be mediated by RNA regulatory elements such as guanine quadruplexes (G-quadruplexes), non-canonical structured RNA motifs that affect RNA stability and translation. Presented in this thesis, we identified the G-quadruplex as a novel endogenous regulator of APP expression within the APP mRNA in its 3'untranslated region at residues 3008-3027 (NM_201414.2). This sequence exhibited characteristics of a parallel G-quadruplex structure as revealed by circular dichroism spectrophotometry. Further, as with other G-quadruplexes, the formation of this structure was dependent on the presence of potassium concentration. Moreover, we present preliminary data demonstrating that FMRP and FXR2P bind to the APP G-quadruplex sequence and regulates it expression.
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Details
- Title
- Characterizing G-quadruplex Mediated Regulation of Amyloid Precursor Protein Expression
- Creators
- Ezekiel Matthew David Crenshaw - DU
- Contributors
- Aleister Saunders (Advisor) - Drexel University (1970-)Michael R. Akins (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
- 7245; 991014632298904721