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Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing
The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct pept...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344212/ https://www.ncbi.nlm.nih.gov/pubmed/25723573 http://dx.doi.org/10.1371/journal.pone.0115369 |
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author | Camargo, Luiz Miguel Zhang, Xiaohua Douglas Loerch, Patrick Caceres, Ramon Miguel Marine, Shane D. Uva, Paolo Ferrer, Marc de Rinaldis, Emanuele Stone, David J. Majercak, John Ray, William J. Yi-An, Chen Shearman, Mark S. Mizuguchi, Kenji |
author_facet | Camargo, Luiz Miguel Zhang, Xiaohua Douglas Loerch, Patrick Caceres, Ramon Miguel Marine, Shane D. Uva, Paolo Ferrer, Marc de Rinaldis, Emanuele Stone, David J. Majercak, John Ray, William J. Yi-An, Chen Shearman, Mark S. Mizuguchi, Kenji |
author_sort | Camargo, Luiz Miguel |
collection | PubMed |
description | The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the “regulatory landscape” of APP. |
format | Online Article Text |
id | pubmed-4344212 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-43442122015-03-04 Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing Camargo, Luiz Miguel Zhang, Xiaohua Douglas Loerch, Patrick Caceres, Ramon Miguel Marine, Shane D. Uva, Paolo Ferrer, Marc de Rinaldis, Emanuele Stone, David J. Majercak, John Ray, William J. Yi-An, Chen Shearman, Mark S. Mizuguchi, Kenji PLoS One Research Article The progressive aggregation of Amyloid-β (Aβ) in the brain is a major trait of Alzheimer's Disease (AD). Aβ is produced as a result of proteolytic processing of the β-amyloid precursor protein (APP). Processing of APP is mediated by multiple enzymes, resulting in the production of distinct peptide products: the non-amyloidogenic peptide sAPPα and the amyloidogenic peptides sAPPβ, Aβ40, and Aβ42. Using a pathway-based approach, we analyzed a large-scale siRNA screen that measured the production of different APP proteolytic products. Our analysis identified many of the biological processes/pathways that are known to regulate APP processing and have been implicated in AD pathogenesis, as well as revealing novel regulatory mechanisms. Furthermore, we also demonstrate that some of these processes differentially regulate APP processing, with some mechanisms favouring production of certain peptide species over others. For example, synaptic transmission having a bias towards regulating Aβ40 production over Aβ42 as well as processes involved in insulin and pancreatic biology having a bias for sAPPβ production over sAPPα. In addition, some of the pathways identified as regulators of APP processing contain genes (CLU, BIN1, CR1, PICALM, TREM2, SORL1, MEF2C, DSG2, EPH1A) recently implicated with AD through genome wide association studies (GWAS) and associated meta-analysis. In addition, we provide supporting evidence and a deeper mechanistic understanding of the role of diabetes in AD. The identification of these processes/pathways, their differential impact on APP processing, and their relationships to each other, provide a comprehensive systems biology view of the “regulatory landscape” of APP. Public Library of Science 2015-02-27 /pmc/articles/PMC4344212/ /pubmed/25723573 http://dx.doi.org/10.1371/journal.pone.0115369 Text en © 2015 Camargo et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Camargo, Luiz Miguel Zhang, Xiaohua Douglas Loerch, Patrick Caceres, Ramon Miguel Marine, Shane D. Uva, Paolo Ferrer, Marc de Rinaldis, Emanuele Stone, David J. Majercak, John Ray, William J. Yi-An, Chen Shearman, Mark S. Mizuguchi, Kenji Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title | Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title_full | Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title_fullStr | Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title_full_unstemmed | Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title_short | Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing |
title_sort | pathway-based analysis of genome-wide sirna screens reveals the regulatory landscape of app processing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344212/ https://www.ncbi.nlm.nih.gov/pubmed/25723573 http://dx.doi.org/10.1371/journal.pone.0115369 |
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