Abstract.
Inhibiting the production of amyloid-β by antagonising γ-secretase activity is currently being pursued as a therapeutic strategy for Alzheimer’s disease (AD). However, early pre-clinical studies have demonstrated that disruption of presenilin-dependent γ-secretase alters many presenilin-dependent processes, leading to early lethality in several AD model organisms. Subsequently, transgenic animal studies have highlighted several gross developmental side effects arising from presenilin deficiency. Partial knockdown or tissue-specific knockout of presenilins has identified the skin, vascular and immune systems as very sensitive to loss of presenilin functions. A more appreciative understanding of presenilin biology is therefore demanded if γ-secretase is to be pursued as a therapeutic target. Herein we review the current understanding of γ-secretase complexes; their regulation, abundance of interacting partners and diversity of substrates. We also discuss regulation of the γ-secretase complexes, with an emphasis on the functional role of presenilins in cell biology.
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Received 25 July 2008; received after revision 24 November 2008; accepted 10 December 2008
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McCarthy, J.V., Twomey, C. & Wujek, P. Presenilin-dependent regulated intramembrane proteolysis and γ-secretase activity. Cell. Mol. Life Sci. 66, 1534–1555 (2009). https://doi.org/10.1007/s00018-009-8435-9
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DOI: https://doi.org/10.1007/s00018-009-8435-9