Presenilin-dependent expression of STIM proteins and dysregulation of capacitative Ca²⁺ entry in familial Alzheimer's disease

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• 作者：Lukasz Bojarski ; Pawel Pomorski ; Aleks ; ra Szybinska ; Mirosł ; aw Drab ; Anna Skibinska-Kijek ; Joanna Gruszczynska-Biegala ; Jacek Kuznicki
• 关键词：Alzheimer's disease ; Capacitative Ca²⁺ entry (CCE) ; Store operated Ca²⁺ entry (SOCE) ; Presenilin ; STIM1 ; STIM2
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
• 出版年：2009
• 出版时间：June 2009
• 年：2009
• 卷：1793
• 期：6
• 页码：1050-1057
• 全文大小：859 K

文摘

Mutations in presenilin 1 (PS1), which are the major cause of familial Alzheimer's disease (FAD), are involved in perturbations of cellular Ca²⁺ homeostasis. Attenuation of capacitative Ca²⁺ entry (CCE) is the most often observed alteration of Ca²⁺ homeostasis in cells bearing FAD PS1 mutations. However, molecular mechanisms underlying this CCE impairment remains elusive. We demonstrate that cellular levels of STIM1 and STIM2 proteins, which are key players in CCE, depend on presenilins. We found increased level of STIM1 and decreased level of STIM2 proteins in mouse embryonic fibroblasts lacking presenilins. Fura-2 ratiometric assays revealed that CCE is enhanced in these cells after Ca²⁺ stores depletion by thapsigargin treatment. In turn, overexpression of PS1 with FAD mutations in HEK293 cells led to an attenuation of CCE. Although, no changes in STIM protein levels were observed in these HEK293 cells, FAD mutations in endogenous PS1 in human B lymphocytes resulted in a decreased expression of STIM2 in parallel to an attenuation of CCE. Our experiments showing that knock-out of presenilins in MEF cells and FAD mutations in endogenous PS1 in lymphocytes affect both CCE and the cellular level of STIM proteins open new perspectives for studies on CCE in FAD.