New publication

A new paper which introduced the original idea of clustering pathways and other biological themes was published on PLOS ONE. The supplementary pages were also created using TargetMine.

Pathway-Based Analysis of Genome-Wide siRNA Screens Reveals the Regulatory Landscape of App Processing

Camargo LM1, Zhang XD2, Loerch P1, Caceres RM1, Marine SD3, Uva P4, Ferrer M3, Rinaldis E4, Stone DJ5, Majercak J5, Ray WJ5, Chen YA6, Shearman MS1, Mizuguchi K6.

1Merck Research Laboratories, Merck & Co, Boston, United States of America.
2Merck Research Laboratories, Merck & Co, Beijing, China.
3Merck Research Laboratories, Merck & Co, North Wales, United States of America.
4Merck Research Laboratories, Instituto di Recerca di Biologia Molecolare, Pomezia, Italy.
5Merck Research Laboratories, Merck & Co, West Point, United States of America.
6National Institute of Biomedical Innovation, Osaka, Japan.

Abstract

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.

PubMed ID: 25723573

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