Regulation of ryanodine receptor-mediated calcium signaling by presenilins

Andrew J. Payne, Simon Kaja, Peter Koulen


Ca2+ dyshomeostasis is a critical causative mechanism underlying the functional impairment of the central nervous system seen in ‘healthy’ aging [1], specifically in normal brain aging processes in the absence of disease-causing mutations or external causes. It is generally thought that such impairments result from the gradual accumulation of small changes at the molecular level, such as oxidative damage to the structure and function of synapses, that ultimately cause the loss of biological function [2].  Alzheimer’s disease (AD) is a multifactorial pathology directly related to aging and with age as a primary risk factor [3].  Neurons affected by AD have an elevated cytosolic calcium ion concentration [4].  It has not yet been determined if the observed elevation of cytosolic calcium is contributing to or results from AD pathology, but there is mounting evidence in support of the Calcium Hypothesis of brain aging [4-9].  The two presenilin genes found in vertebrates are ubiquitously expressed as the transmembrane proteins presenilin-1 (PS1) and presenilin-2 (PS2), respectively, in the endoplasmic reticulum (ER). They  are part of the γ-secretase enzyme complex catalyzing the processing of amyloid precursor protein (APP), which - if aberrant under disease conditions - can result in the generation of neurotoxic amyloid-beta (Aβ) peptides [10] (Fig. 1).  Approximately 80% of the mutations linked to familial AD have been found in PS1 [11] and clinically relevant PS1 mutations exert effects on cytosolic calcium concentrations [10, 12].  While both presenilins affect cytosolic calcium concentrations, the PS1 isoform binds to several proteins essential to the regulation of intracellular calcium signaling, e.g. the inositol 1,4,5-trisphosphate receptor (IP3R) [13], the N-methyl-D-aspartate (NMDA) receptor (NMDAR) [14], and the ryanodine receptor (RyR) [15-17].  Here, the interaction of presenilins with RyRs will be reviewed.


PMID: 25646163 [PubMed]

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