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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
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.
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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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