Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons

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Abstract

Presenilins regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease. Elevated presenilin-1 (PS1) holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer disease (FAD) PS1 mutations. This study examines the effect of the FAD presenilin mutant that lacks the ninth exon (PS1 ∆E9) and does not undergo endoproteolysis on store-operated calcium (SOC) entry. Significant enhancement of SOC channel activation was detected by electrophysiological measurements in hippocampal neurons with PS1 ∆E9 mutant expression. Here, we show that (i) the hyperactivation of SOC channels is mediated by the STIM1 sensor and can be attenuated by STIM1 knockdown or 2-aminoethoxydiphenyl borate application, (ii) the STIM2 is not involved in pathological changes of SOC entry, (iii) the pathological SOC entry demonstrates properties of both TRPC and Orai subunit composition, and (iiii) transgenic Drosophila flies with PS1 ∆E9 expression in the cholinergic neuron system show short-term memory loss, which can be abolished by 2-aminoethoxydiphenyl borate feeding.

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Acknowledgments

We wish to thank Dr. I. Bezprozvanny (Southwestern Medical Center, Dallas, TX) for providing us with human wild-type PS1 and PS1 ∆E9 expression plasmids. We thank Dr. Stefanie Weidtkamp-Peters from Heinrich-Heine-Universität Düsseldorf, Center for Advanced Imaging (CAi), who helped with live-cell imaging and Dr. Yuri Kaulin for his help in preparing the manuscript. This work was supported by the Russian Scientific Foundation, project no. 14-14-00720 (to M.R. and E.K.), the program of “Molecular and Cellular Biology” RAS (to K.S), the Russian Basic Research Foundation, ERAnet RUS (to A.M. and E.K.), the OPTEC LLC and the President of Russia Scholarship (to M.R.).

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M.R. performed and designed the research, analyzed the data, and wrote the paper; A.G. performed the research and analyzed the data; K.S. performed the research and analyzed the data, M.E. performed the research; A.M. and P.G. designed the research; and E.K. designed the research and wrote the paper.

Corresponding authors

Correspondence to Maria Ryazantseva or Elena Kaznacheyeva.

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Ryazantseva, M., Goncharova, A., Skobeleva, K. et al. Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons. Mol Neurobiol 55, 4667–4680 (2018). https://doi.org/10.1007/s12035-017-0674-4

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Keywords

  • Alzheimer’s disease
  • STIM1
  • SOC
  • Drosophila
  • Calcium
  • Calcium channel