The γ-Secretase Protease Complexes in Neurodegeneration, Cancer and Immunity

  • Caroline Coleman-Vaughan
  • Arijit Mal
  • Abhijit De
  • Justin V. McCarthyEmail author


The intramembrane-cleaving proteases (I-CliPs) are necessary for the proteolytic cleavage of several transmembrane proteins and initiation of divergent signalling events. The tetrameric γ-secretase protease complexes, comprised of presenilin and three other subunits, represent a major subclass of the I-CliPs. The γ-secretase protease complexes are involved in regulated intramembrane proteolysis, an evolutionary conserved and important signal transduction process encompassing the sequential proteolysis of transmembrane substrates that are central to many physiological processes, including embryonic development, haematopoiesis, and normal functioning of the nervous and immune systems. Deregulated intramembrane proteolysis of certain substrates is proposed to be associated with neurodegeneration, cancer and impaired immune function. In this chapter, we summarise the major biochemical and functional properties (structure, catalytic mechanisms, substrate specificities, and regulation) of the γ-secretase protease complexes. We also present evidence for a role of γ-secretase protease complexes in neurodegeneration, cancer and inflammatory disease and consider the use of γ-secretase inhibitors as prospective therapeutics in several diseases.


γ-secretase protease Regulated intramembrane proteolysis Presenilin Neurodegeneration Alzheimer’s disease Cancer Innate immune signalling Immunity Signalling γ-secretase inhibitor 



We apologise to all colleagues whose work has not been discussed or cited owing to space limitations. This work was supported and funded by grants from Science Foundation Ireland (02/IN1/B218 and 09/IN.1/B2624) and a student bursary to CCV from the College of Science Engineering & Food Science, University College Cork.


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Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  • Caroline Coleman-Vaughan
    • 1
  • Arijit Mal
    • 2
  • Abhijit De
    • 2
  • Justin V. McCarthy
    • 1
    • 3
    Email author
  1. 1.Signal Transduction Laboratory, School of Biochemistry & Cell BiologyUniversity College CorkCorkIreland
  2. 2.Molecular Functional Imaging LaboratoryAdvanced Centre for Treatment, Research and Education in Cancer, Tata Memorial CentreKhargharIndia
  3. 3.School of Biochemistry & Cell BiologyUniversity College CorkCorkIreland

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