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Journal article
Amyloid Precursor Protein Translation Is Regulated by a 3 ' UTR Guanine Quadruplex
PloS one, v 10(11)
30 Nov 2015
PMID: 26618502
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 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. Via a bioinformatics approach, we identified a candidate G-quadruplex within the APP mRNA in its 3' UTR (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 ions. This G-quadruplex has no apparent role in regulating transcription or mRNA stability as wild type and mutant constructs exhibited equivalent mRNA levels as determined by real time PCR. Instead, we demonstrate that this G-quadruplex negatively regulates APP protein expression using dual luciferase reporter and Western blot analysis. Taken together, our studies reveal post-transcriptional regulation by a 3' UTR G-quadruplex as a novel mechanism regulating APP expression.
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Details
- Title
- Amyloid Precursor Protein Translation Is Regulated by a 3 ' UTR Guanine Quadruplex
- Creators
- Ezekiel Crenshaw - Drexel UniversityBrian P. Leung - Drexel UniversityChun Kit Kwok - Pennsylvania State UniversityMichal Sharoni - Drexel UniversityKalee Olson - Pennsylvania State UniversityNeeraj P. Sebastian - Drexel UniversitySara Ansaloni - Drexel UniversityReinhard Schweitzer-Stenner - Drexel UniversityMichael R. Akins - Drexel UniversityPhilip C. Bevilacqua - Pennsylvania State UniversityAleister J. Saunders - Drexel University
- Publication Details
- PloS one, v 10(11)
- Publisher
- Public Library Science
- Number of pages
- 18
- Grant note
- R01NS057295; R36AG048247; R00MH90237 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA RGP0002/2009-C / Human Frontier Science Program grant; Human Frontier Science Program Cure Alzheimer's Fund R01NS057295 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) K12GM081259 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) R36AG048247 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) R00MH090237 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000365889800026
- Scopus ID
- 2-s2.0-84957603024
- Other Identifier
- 991019167816104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology