Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines

Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of γ-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering γ-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of a soluble, cytosolic N-terminal domain fragment (NTF) of PS to intracellular Ca2+ release channels, ryanodine receptors (RyR), controls Ca2+ release from the ER. While PS1NTF decreased total RyR-mediated Ca2+ release, PS2NTF had no effect at physiological Ca2+ concentrations. This differential function and isotype-specificity is due to four cysteines absent in PS1NTF, present, however, in PS2NTF. Site-directed mutagenesis targeting these cysteines converted PS1NTF to PS2NTF function and vice versa, indicating differential RyR binding. This novel mechanism of intracellular Ca2+ regulation through the PS–RyR interaction represents a novel target for AD drug development and the treatment of other neurodegenerative disorders that critically depend on RyR and PS signaling. •Novel mechanism: presenilin N-termini control intracellular calcium release.•Isotype-specific effect due to 4 cysteines is absent in presenilin 1 and present in presenilin 2.•Mutagenesis converted function of presenilins 1 to 2 and vice versa.•Novel target for Alzheimer's disease drug development and treatment of neurodegeneration