A Fast Growing Spectrum of Biological Functions of γ-secretase in Development and Disease

Biochim Biophys Acta. 2013 Dec;1828(12):2815-27. doi: 10.1016/j.bbamem.2013.04.016.


γ-secretase, which assembles as a tetrameric complex, is an aspartyl protease that proteolytically cleaves substrate proteins within their membrane-spanning domain; a process also known as regulated intramembrane proteolysis (RIP). RIP regulates signaling pathways by abrogating or releasing signaling molecules. Since the discovery, already >15 years ago, of its catalytic component, presenilin, and even much earlier with the identification of amyloid precursor protein as its first substrate, γ-secretase has been commonly associated with Alzheimer's disease. However, starting with Notch and thereafter a continuously increasing number of novel substrates, γ-secretase is becoming linked to an equally broader range of biological processes. This review presents an updated overview of the current knowledge on the diverse molecular mechanisms and signaling pathways controlled by γ-secretase, with a focus on organ development, homeostasis and dysfunction. This article is part of a Special Issue entitled: Intramembrane Proteases.

Keywords: APP; Alzheimer; Notch; Presenilin; γ-Secretase, regulated intramembrane proteolysis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alzheimer Disease / enzymology
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / chemistry
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Embryo, Mammalian
  • Gene Expression Regulation, Developmental*
  • Homeostasis
  • Humans
  • Morphogenesis / genetics*
  • Presenilin-1 / chemistry
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism*
  • Protein Multimerization
  • Protein Subunits / chemistry
  • Protein Subunits / genetics
  • Protein Subunits / metabolism*
  • Proteolysis
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Signal Transduction*
  • Substrate Specificity


  • Amyloid beta-Protein Precursor
  • Presenilin-1
  • Protein Subunits
  • Receptors, Notch
  • Amyloid Precursor Protein Secretases