Presenilin-ryanodine receptor connection.

The Presenilins (PS) gene family is composed of two members: PS1 and PS2. Mutations in PSs are linked to familial Alzheimer’s disease (FAD) (1). PSs are the catalytic subunits of the γ-secretase multimolecular complex, which mediates the intramembranous cleavage of many type I membrane proteins, including amyloid precursor protein (APP) and Notch (2, 3). Cleavage of substrates produces secreted and intracellular peptides, which in many cases are involved in intracellular signaling pathways. Although the γ-secretase activity of PS is widely characterized, γsecretase–independent activities have also been described. PS inactivation leads to impaired memory and neurodegeneration (3–5), two key features of Alzheimer’s disease (AD). Although the importance of PSs in AD is well established, their precise contribution to normal brain function and to FAD pathogenesis are less clear. PSs are expressed in all tissues and cell types. Given the association of PS with FAD, much attention has been paid to the physiological and pathological role of PSs in the brain. Robust experimental evidence indicates that PSs regulate neurotransmitter release at synapses and intracellular Ca homeostasis. However, how exactly this regulation takes place is not fully understood. In PNAS, a study by Wu et al. (5) provides evidence for a unique mechanism by which PSs can control both intracellular Ca and transmitter release. Although neurotransmitter release is normally triggered by Ca influx into the presynaptic terminal via voltage-gated Ca channels (VGCCs), Ca release from intracellular stores may also participate (6, 7). The endoplasmic reticulum (ER) is a major intracellular Ca store that can be found in presynaptic terminals (6). Cytosolic Ca is pumped into the ER by sarco-ER Ca ATPase (SERCA), whereas Ca release from the ER is mediated by two main types of receptors: ryanodine receptors (RyRs), which mediate Ca-induced Ca release (CICR), and inositol-1,4,5-triphosphate receptors (IP3Rs). PSs have been linked to regulation of ER Ca metabolism. However, previous studies generated conflicting results as to whether PS increases or decreases Ca concentration in the ER and whether (and how) it interacts functionally with Ca regulators in the ER (3, 8). It has been proposed that PSs function as ER Ca leak channels (9), as activators of IP3R-mediated Ca 2+ release from the ER (10), or activators of SERCA (11). Despite all these somewhat conflicting data, there is evidence that PSs are important regulators of Ca homeostasis in neurons and that perturbed Ca homeostasis could play a key role in the pathogenesis of AD (12). By genetically inactivating in mice in either preor postsynaptic neurons of the hippocampus, which is a key brain area involved in memory formation, Shen Fig. 1. Possible γ-secretase–dependent and –independent mechanisms by which PSs regulate RyR levels and synaptic function. PS1 could promote maturation and stability of RyR proteins interacting with RyRs in the ER to facilitate their maturation and targeting to synapses (ER chaperon activity) (1). Processing by the PS-dependent γ-secretase multimolecular complex—formed by Aph1, Pen2, Nct, and either PS1 or PS2—of an undefined transmembrane protein could release an ER domain (ERD) peptide that assists maturation and/or stabilization of RyR proteins (2). An intracellular domain (ICD) peptide released by γ-processing of an undefined transmembrane protein could deliver an intracellular signal that promotes RyRs mRNA translation and/or RyRs protein stability (3). PSs could regulate RyRs mRNA translation and/or RyRs protein stability via a still unknown γ-secretase–independent mechanism (4). These functions are impaired by PS deletion, leading to reduced levels and function of RyRs at the presynaptic termini (5). Author contributions: L.D. and P.E.C. wrote the paper.