Presenilins: Role in calcium homeostasis

Mutations in presenilins are responsible for the vast majority of early-onset familial Alzheimer's disease cases. Full-length presenilin structure is composed of nine transmembrane domains which are localized on the endoplasmic reticulum membrane. Upon endoproteolytic cleavage, presenilins assemble into the gamma-secretase multiprotein complex and subsequently get transported to the cell surface. There is a wealth of knowledge around the role of presenilins as the catalytic component of gamma-secretase, their involvement in amyloid precursor protein processing and generation of neurotoxic beta-amyloid species. However recent findings have revealed a wide range of gamma-secretase-independent presenilin functions, including involvement in calcium homeostasis. Particularly, familial Alzheimer's disease presenilin mutations have been shown to interfere with the function of several molecular elements involved in endoplasmic reticulum calcium homeostasis. Presenilins modulate the activity of IP3 and Ryanodine receptor channels, regulate SERCA pump function, affect capacitative calcium entry and function per se as endoplasmic reticulum calcium leak conductance pores. (c) 2012 Published by Elsevier Ltd.