Institute of Cytology, Russian Academy of Sciences, 4 Tikhoretsky Ave, St. Petersburg, 194064, Russia.
Pavlov Institute of Physiology, Russian Academy of Sciences, 6 Makarova emb, St. Petersburg, 199034, Russia.
Mol Neurobiol. 2018 Jun;55(6):4667-4680. doi: 10.1007/s12035-017-0674-4. Epub 2017 Jul 13.
Presenilins regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer disease. Elevated presenilin-1 (PS1) holoprotein levels have been detected in postmortem brains of patients carrying familial Alzheimer disease (FAD) PS1 mutations. This study examines the effect of the FAD presenilin mutant that lacks the ninth exon (PS1 ∆E9) and does not undergo endoproteolysis on store-operated calcium (SOC) entry. Significant enhancement of SOC channel activation was detected by electrophysiological measurements in hippocampal neurons with PS1 ∆E9 mutant expression. Here, we show that (i) the hyperactivation of SOC channels is mediated by the STIM1 sensor and can be attenuated by STIM1 knockdown or 2-aminoethoxydiphenyl borate application, (ii) the STIM2 is not involved in pathological changes of SOC entry, (iii) the pathological SOC entry demonstrates properties of both TRPC and Orai subunit composition, and (iiii) transgenic Drosophila flies with PS1 ∆E9 expression in the cholinergic neuron system show short-term memory loss, which can be abolished by 2-aminoethoxydiphenyl borate feeding.
早老素蛋白调节内质网中的钙离子稳态，细胞内钙离子的失调与阿尔茨海默病的发病机制有关。在携带家族性阿尔茨海默病（FAD）早老素 1 （PS1）突变的患者死后的大脑中检测到早老素 1 （PS1）全蛋白水平升高。本研究探讨了缺乏第九外显子（PS1 ∆E9）且不进行内肽酶切割的 FAD 早老素突变体对储存操作钙（SOC）进入的影响。通过在表达 PS1 ∆E9 突变体的海马神经元中的电生理测量，检测到 SOC 通道激活的显著增强。在这里，我们表明：（i）SOC 通道的超激活是由 STIM1 传感器介导的，可以通过 STIM1 敲低或 2-氨基乙氧基二苯硼酸盐的应用来减弱；（ii）STIM2 不参与 SOC 进入的病理性改变；（iii）病理性 SOC 进入表现出 TRPC 和 Orai 亚基组成的特性；（iiii）在胆碱能神经元系统中表达 PS1 ∆E9 的转基因果蝇表现出短期记忆丧失，这种记忆丧失可以通过 2-氨基乙氧基二苯硼酸盐喂养来消除。
