Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.
Lysosome and calcium dysregulation in Alzheimer's disease: partners in crime.
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阿尔茨海默病中的溶酶体和钙失调：犯罪伙伴。
DOI：
10.1042/bst20130201
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发表时间：
2013-12
影响因子：
3.9
通讯作者：
Nixon RA
中科院分区：
文献类型：
--
作者：
McBrayer M;Nixon RA
早发性家族性阿尔茨海默病(FAD)是由早老素1、早老素2和淀粉样前体蛋白突变引起的。除了PS1突变对γ-分泌酶复合体的蛋白分解功能的影响外，突变或缺陷的PS1还会破坏溶酶体功能和钙稳态，这两个因素都被认为是FAD的强烈致病因素。PS1功能的丧失损害了溶酶体上空泡ATPase的组装和质子泵活性，导致溶酶体酸化缺陷和显著的自噬功能障碍。突变体PS1在FAD中对细胞钙的额外失调被归因于内质网离子通道的改变；然而，继发于溶酶体酸化缺陷的PS1缺陷细胞也异常地释放了溶酶体中丰富的钙储存。由此产生的胞浆钙升高激活了钙依赖的酶，大大促进了钙蛋白的过度激活，这是导致所有形式的AD的神经原纤维变性的最终共同途径。在这里，我们讨论了溶酶体功能缺陷、自噬和钙稳态作为PS1相关性FAD的致病过程之间的密切关系，以及它们与散发性AD的相关性。
Early onset familial Alzheimer’s disease (FAD) is caused by mutations of Presenilin 1, Presenilin 2, and amyloid precursor protein. Beyond the effects of PS1 mutations on proteolytic functions of the gamma-secretase complex, mutant or deficient PS1 disrupts lysosomal function and calcium homeostasis, both of which are considered strong pathogenic factors in FAD. Loss of PS1 function compromises assembly and proton-pumping activity of the vacuolar-ATPase on lysosomes, leading to defective lysosomal acidification and marked impairment of autophagy. Additional dysregulation of cellular calcium by mutant PS1 in FAD has been ascribed to altered ion channels in the endoplasmic reticulum; however, rich stores of calcium in lysosomes are also abnormally released in PS1-deficient cells secondary to the lysosomal acidification defect. The resultant rise in cytosolic calcium activates calcium-dependent enzymes, contributing substantially to calpain over-activation that is a final common pathway leading to neurofibrillary degeneration in all forms of AD. Here we discuss the close inter-relationships among deficits of lysosomal function, autophagy, and calcium homeostasis as a pathogenic process in PS1-related FAD and their relevance to sporadic AD.