Dominant Effect of Full-Length Presenilin-1 on the Enhancement of Store-Operated Calcium Entry

Abstract

Familial Alzheimer’s disease is a severe neurodegenerative disorder. Mutations in the presenilin-1 (PS1) gene account for most familial Alzheimer’s disease cases. Normally, PS1 is cleaved to 2 terminal fragments to form an enzyme center of the γ-secretase complex. A significant number of mutations in the gene of PS1 protein leads to impairment of its endoproteolysis and full-length PS1 accumulation. The deletion of 9th exon of the PS1 gene associated with Alzheimer’s disease results in the loss of the endoproteolytic cleavage site and the PS1 holoprotein accumulation. Alzheimer’s disease is often associated with disruption of calcium homeostasis. Different cellular and molecular models demonstrate changes in the calcium store content and, accordingly, a deregulation of the store-operated calcium entry. In the current study we demonstrate that PS1 with deletion of the 9th exon (PS1 ΔE9) and mutant PS1 D257A, which are not subjected to proteolytic cleavage, accumulate in cells as holoproteins. The PS1 mutant accumulation led to an increase in the store-operated calcium entry. At the same time, the expression of the PS1 terminal fragments did not affect store-operated calcium entry. Overall, the increase in the store-operated calcium entry in cell models of the familial Alzheimer’s disease is caused by a dominant effect of the PS1 holoprotein accumulation independently of its γ-secretase activity.