Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide
Alzheimer's PS-1 mutation perturbs calcium homeostasis and sensitizes PC12 cells to death induced by amyloid beta-peptide
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DOI：
10.1097/00001756-199612200-00074
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发表时间：
1996-12-20
期刊：
影响因子：
1.7
通讯作者：
MAttson, MP
中科院分区：
文献类型：
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作者：
Guo, Q;Furukawa, K;MAttson, MP
14号染色体早老素-1（PS-1）基因突变与常染色体显性早发性阿尔茨海默病有关。PS-1的氨基酸序列预测一个完整的膜蛋白和免疫细胞化学研究表明，PS-1定位于内质网（ER）。我们报告，PS-1突变L286 V在培养的PC 12细胞中的表达夸大了Ca 2+的反应，激动剂（卡巴胆碱和缓激肽），诱导Ca 2+从ER释放。表达L286 V的细胞在暴露于淀粉样β-肽（A（B）eta）后表现出[Ca 2 +]（i）的增强的升高和对A β毒性的增加的脆弱性。电压依赖性钙通道的拮抗剂（硝苯地平）和ER释放Ca 2+的阻滞剂（丹曲林）可抵消PS-1突变的不良后果。通过扰乱Ca 2+稳态，PS-1突变可能使神经元对A β诱导的细胞凋亡敏感。
MUTATIONS in the presenilin-1 (PS-1) gene on chromosome 14 are linked to autosomal dominant early-onset Alzheimer's disease. The amino acid sequence of PS-1 predicts an integral membrane protein and immunocytochemical studies indicate that PS-1 is localized to endoplasmic reticulum (ER). We report that expression of PS-1 mutation L286V in cultured PC12 cells exaggerates Ca2+ responses to agonists (carbachol and bradykinin) that induce Ca2+ release from ER. Cells expressing L286V exhibit enhanced elevations of [Ca2+](i) following exposure to amyloid beta-peptide (A(b)eta) and increased vulnerability to A beta toxicity. An antagonist of voltage-dependent calcium channels (nifedipine), and a blocker of Ca2+ release from ER (dantrolene), counteract the adverse consequences of the PS-1 mutation. By perturbing Ca2+ homeostasis, PS-1 mutations may sensitize neurons to A beta-induced apoptosis.