Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
Amyloid precursor protein processing in human neurons with an allelic series of the PSEN1 intron 4 deletion mutation and total presenilin-1 knockout
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DOI：
10.1093/braincomms/fcz024
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Wray, Selina
中科院分区：
文献类型：
--
作者：
Arber, Charles;Villegas-Llerena, Claudio;Wray, Selina
编码淀粉样前体蛋白加工酶γ-分泌酶催化亚基的早老蛋白-1 (PSEN1) 的突变会导致家族性阿尔茨海默病。然而，疾病的机制尚未完全了解，并且突变是否主要通过功能的获得或丧失来发挥作用仍然存在争议。为了解决这个问题，我们生成了 PSEN1 突变内含子 4 缺失的等基因等位基因系列；以对照、杂合子和纯合突变体诱导的多能干细胞以及早老素-1敲除系为代表。诱导多能干细胞来源的皮层神经元显示，早老素 1 敲除系中淀粉样蛋白 β 水平降低，但可检测到；PSEN1 内含子 4 缺失系中淀粉样前体蛋白加工存在突变基因剂量依赖性缺陷，这与 γ 分泌酶持续合成能力降低一致。 presenilin-1 敲除和 PSEN1 内含子 4 缺失突变对淀粉样前体蛋白 C99 片段积累、尼卡斯特林成熟和淀粉样蛋白 β 肽生成的不同影响支持家族性阿尔茨海默病相关突变和 presenilin-1 敲除对 γ 分泌酶功能的不同影响。
Mutations in presenilin-1 (PSEN1), encoding the catalytic subunit of the amyloid precursor protein-processing enzyme gamma-secretase, cause familial Alzheimer's disease. However, the mechanism of disease is yet to be fully understood and it remains contentious whether mutations exert their effects predominantly through gain or loss of function. To address this question, we generated an isogenic allelic series for the PSEN1 mutation intron 4 deletion; represented by control, heterozygous and homozygous mutant induced pluripotent stem cells in addition to a presenilin-1 knockout line. Induced pluripotent stem cell-derived cortical neurons reveal reduced, yet detectable amyloid-beta levels in the presenilin-1 knockout line, and a mutant gene dosage-dependent defect in amyloid precursor protein processing in PSEN1 intron 4 deletion lines, consistent with reduced processivity of gamma-secretase. The different effects of presenilin-1 knockout and the PSEN1 intron 4 deletion mutation on amyloid precursor protein-C99 fragment accumulation, nicastrin maturation and amyloid-beta peptide generation support distinct consequences of familial Alzheimer's disease-associated mutations and knockout of presenilin-1 on the function of gamma-secretase.