Using a genetically targeted sensor to investigate the role of presenilin-1 in ER Ca2+ levels and dynamics

The ER plays a fundamental role in storing cellular Ca2+, generating Ca2+ signals, and modulating Ca2+ in both the cytosol and mitochondria. Genetically encoded Ca2+ sensors can be explicitly targeted to the ER to directly define Ca2+ levels and monitor fluxes of Ca2+ within this organelle. In this study we use an ER-targeted Ca2+ sensor to define both the level and dynamics of ER Ca2+ in cells expressing mutant presenilin proteins. Growing evidence suggests the enigmatic presenilin-1 plays a role in regulating ER Ca2+. Presenilin-1 was initially identified in a screen for genetic causes of inherited familial Alzheimer's disease (fAD). The connection between presenilin-1, calcium regulation, and Alzheimer's disease may provide the key to understanding the long-observed, but poorly understood, link between Alzheimer's disease and Ca2+ dysregulation. In this study we examined seven fAD-causing mutations in presenilin-1 to define how they influence ER Ca2+ levels and dynamics. We observed that some, but not all, mutations in PS1 decrease the level of Ca2+ within the ER and this difference depends on the enzymatic activity of PS1. Two mutations tested altered the kinetics of Ca2+ release from the ER upon ATP stimulation, resulting in faster spiking. Combined, these results indicate that mutations in PS1 can alter the balance of Ca2+ in cells and have the potential to influence the nature of Ca2+ signals.