title: Emerging roles of the γ-secretase-notch axis in inflammation.
abstract: γ-Secretase is a distinct proteolytic complex required for the activation of many transmembrane proteins. The cleavage of substrates by γ-secretase plays diverse biological roles in producing essential products for the organism. More than 90 transmembrane proteins have been reported to be substrates of γ-secretase. Two of the most widely known and studied of these substrates are the amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β (Aβ) and the Notch intracellular domain (NICD), respectively. The wide spectrum of γ-secretase substrates has made analyses of the pathology of γ-secretase-related diseases and underlying mechanisms challenging. Inflammation is an important aspect of disease pathology that requires an in-depth analysis. γ-Secretase may contribute to disease development or progression by directly increasing and regulating production of pro-inflammatory cytokines. This review summarizes recent evidence for a role of γ-secretase in inflammatory diseases, and discusses the potential use of γ-secretase inhibitors as an effective future treatment option.
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address: jodg@skku.edu.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000502:physiology*; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases
keywords: Inflammation; Inflammatory diseases; Notch; Stroke; γ-Secretase