title: Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease.
abstract: Mutations in presenilins (PS1 and PS2) account for the vast majority of early onset familial Alzheimer's disease cases. Beside the well investigated role of presenilins as the catalytic unit in γ-secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of Alzheimer's disease research. Here we report that the overexpression of PS1 full-length holoprotein forms, in particular familial Alzheimer's disease-causing forms of PS1, result in significantly attenuated calcium release from thapsigargin- and bradykinin-sensitive stores. Interestingly, treatment of HEK293 cells with γ-secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated PS1 holoprotein levels. Similarly, the knockdown of PEN-2 which is associated with deficient PS1 endoproteolysis and accumulation of its holoprotein form also leads to decreased ER calcium release. Notably, we detected enhanced PS1 holoprotein levels also in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Taken together, the conditions in which the amount of full length PS1 holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed ER calcium homeostasis mediated by the elevation of PS1 holoprotein levels may be a contributing factor to the pathogenesis of Alzheimer's disease.
authors: Department of Translational Brain Research, DZNE - German Center for Neurodegenerative Diseases, Munich, Germany.
authors: Kamran
authors: K
authors: Honarnejad
authors: Christian K E
authors: CK
authors: Jung
authors: Sven
authors: S
authors: Lammich
authors: Thomas
authors: T
authors: Arzberger
authors: Hans
authors: H
authors: Kretzschmar
authors: Jochen
authors: J
authors: Herms
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D016022:Case-Control Studies; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; C469349:PSENEN protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium
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