Presenilin-1 Delta E9 Mutant Induces STIM1-Driven Store-Operated Calcium Channel Hyperactivation in Hippocampal Neurons
- 447 Downloads
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.
KeywordsAlzheimer’s disease STIM1 SOC Drosophila Calcium Calcium channel
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.).
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.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no competing interests.
- 7.Hiltunen M, Helisalmi S, Mannermaa A, Alafuzoff I, Koivisto AM, Lehtovirta M, Pirskanen M, Sulkava R et al (2000) Identification of a novel 4.6-kb genomic deletion in presenilin-1 gene which results in exclusion of exon 9 in a Finnish early onset Alzheimer’s disease family: an Alu core sequence-stimulated recombination? Eur J Hum Genet 8:259–266CrossRefPubMedGoogle Scholar
- 23.Ambudkar IS, de Souza LB, Ong HL (2016) TRPC1, Orai1, and STIM1 in SOCE: friends in tight spaces. Cell Calcium pii S0143-4160(16):30218–30214Google Scholar
- 24.Storch U, Forst AL, Philipp M, Gudermann T, Mederos y Schnitzler, M. (2012) Transient receptor potential channel 1 (TRPC1) reduces calcium permeability in heteromeric channel complexes. J Biol Chem 287:3530–3540Google Scholar
- 25.Strübing C, Krapivinsky G, Krapivinsky L, Clapham DE (2003) Formation of novel TRPC channels by complex subunit interactions in embryonic brain. J Biol Chem 278:39014–39019Google Scholar
- 33.Skibinska-Kijek A, Wisniewska MB, Gruszczynska-Biegala J, Methner A, Kuznicki J (2009) Immunolocalization of STIM1 in the mouse brain. Acta Neurobiol Exp (Wars) 69:413–428Google Scholar
- 46.Mollet P, Graf U, Würgler FE (1974) Toxicity and mutagenicity of dimethyl sulfoxide in two strains of Drosophila melanogaster. Arch Genet (Zur) 47:184–190Google Scholar
- 58.Williams RT, Manji SS, Parker NJ, Hancock MS, Van Stekelenburg L, Eid JP, Senior PV, Kazenwadel JS et al (2001) Identification and characterization of the STIM (stromal interaction molecule) gene family: coding for a novel class of transmembrane proteins. Biochem J 357:673–685CrossRefPubMedPubMedCentralGoogle Scholar