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Pathophysiological Aspects of Proteases pp 47–87Cite as

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

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Abstract

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.

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Acknowledgements

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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Authors and Affiliations

  1. Signal Transduction Laboratory, School of Biochemistry & Cell Biology, University College Cork, ABCRF, Western Gateway Building, Cork, Ireland

    Caroline Coleman-Vaughan & Justin V. McCarthy

  2. Molecular Functional Imaging Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, India

    Arijit Mal & Abhijit De

  3. School of Biochemistry & Cell Biology, University College Cork, ABCRF, 3.41 Western Gateway Building, Western Road, Cork, Ireland

    Justin V. McCarthy

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  1. Caroline Coleman-Vaughan
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  2. Arijit Mal
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Correspondence to Justin V. McCarthy .

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  1. Department of Biochemistry and Biophysics, University of Kalyani, Kalyani, West Bengal, India

    Sajal Chakraborti

  2. Institute of Cardiovascular Sciences, University of Manitoba, Manitoba, Canada

    Naranjan S. Dhalla

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Coleman-Vaughan, C., Mal, A., De, A., McCarthy, J.V. (2017). The γ-Secretase Protease Complexes in Neurodegeneration, Cancer and Immunity. In: Chakraborti, S., Dhalla, N. (eds) Pathophysiological Aspects of Proteases. Springer, Singapore. https://doi.org/10.1007/978-981-10-6141-7_3

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