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Beside the well investigated role of presenilins as the catalytic unit in \u03b3\u2010secretase complex, their involvement in regulation of intracellular calcium homeostasis has recently come into more focus of <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease research. Here we report that the overexpression of <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> full\u2010length holoprotein forms, in particular familial <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease\u2010causing forms of <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content>, result in significantly attenuated calcium release from thapsigargin\u2010 and bradykinin\u2010sensitive stores. Interestingly, treatment of <jats:styled-content style=\"fixed-case\">HEK<\/jats:styled-content>293 cells with \u03b3\u2010secretase inhibitors also leads to decreased amount of calcium release from endoplasmic reticulum (ER) accompanying elevated <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> holoprotein levels. Similarly, the knockdown of <jats:styled-content style=\"fixed-case\">PEN<\/jats:styled-content>\u20102 which is associated with deficient <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> endoproteolysis and accumulation of its holoprotein form also leads to decreased <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> calcium release. Notably, we detected enhanced <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> holoprotein levels also in postmortem brains of patients carrying familial <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> mutations. Taken together, the conditions in which the amount of full length <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> holoprotein is increased result in reduction of calcium release from ER. Based on these results, we propose that the disturbed <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content> calcium homeostasis mediated by the elevation of <jats:styled-content style=\"fixed-case\">PS1<\/jats:styled-content> holoprotein levels may be a contributing factor to the pathogenesis of <jats:styled-content style=\"fixed-case\">A<\/jats:styled-content>lzheimer's disease.<\/jats:p>","DOI":"10.1111\/jcmm.12008","type":"journal-article","created":{"date-parts":[[2013,2,5]],"date-time":"2013-02-05T09:07:14Z","timestamp":1360055234000},"page":"293-302","source":"Crossref","is-referenced-by-count":26,"title":["Involvement of presenilin holoprotein upregulation in calcium dyshomeostasis of Alzheimer's disease"],"prefix":"10.1111","volume":"17","author":[{"given":"Kamran","family":"Honarnejad","sequence":"first","affiliation":[{"name":"Department of Translational Brain Research DZNE \u2013 German Center for Neurodegenerative Diseases Munich Germany"},{"name":"Center for 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