Open AccessInvolvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease
Author(s) -
Honarnejad Kamran,
Jung Christian K.E.,
Lammich Sven,
Arzberger Thomas,
Kretzschmar Hans,
Herms Jochen
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12008
Subject(s) - presenilin , downregulation and upregulation , calcium , alzheimer's disease , neuroscience , chemistry , disease , medicine , pathology , biology , biochemistry , gene
Abstract Mutations in presenilins ( PS1 and PS2 ) account for the vast majority of early onset familial A lzheimer'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 A lzheimer's disease research. Here we report that the overexpression of PS1 full‐length holoprotein forms, in particular familial A lzheimer's disease‐causing forms of PS1 , result in significantly attenuated calcium release from thapsigargin‐ and bradykinin‐sensitive stores. Interestingly, treatment of HEK 293 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 A lzheimer'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 A lzheimer's disease.