Presenilin-2 modulation of ER-mitochondria interactions

Abstract

P resenilin (PS) mutations are the main cause of Familial Alzheimer’s Disease (FAD) and have been demonstrated to cause an imbalance of intracellular Ca2+ homeostasis. Though PS1 and 2 are gen- erally considered to behave similarly in terms of their effects on Ca2+ handling, we have recently described a novel func- tion, which is unique to PS2, i.e., the modulation of ER-mitochondria juxta- position. Accordingly, PS2, but not PS1, affects the Ca2+ cross-talk between these organelles, a key feature in determining cell fate. In particular, PS2 overexpres- sion, and more drastically that of FAD- linked PS2 mutants, strongly increases the interaction between ER and mito- chondria, thus facilitating mitochondrial Ca2+ uptake. The likely mechanisms behind this phenomenon and its poten- tial effects in cell physiology and pathol- ogy are discussed. Presenilins