Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization
Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization
复制标题
中国早发阿尔茨海默病家系中两种新的早老蛋白-1突变（I249L和P433S）及其功能特征
DOI：
10.1016/j.bbrc.2019.05.185
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Jia J.
中科院分区：
文献类型：
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作者：
Shen L;Qin W;Wu L;Zhou A;Tang Y;Wang Q;Jia L;Jia J.
对早老素-1（PSEN 1）突变的临床研究和功能分析有助于揭示PSEN 1在阿尔茨海默病（AD）发病机制中的作用。通过对两个中国阿尔茨海默病家系的PSEN 1、早老素-2和淀粉样前体蛋白基因的突变筛查，我们发现了两个新的PSEN 1突变，I249和P433 S。两名先证者表现为进行性记忆力下降和随后的精神症状，发病年龄分别为54岁和34岁。在用表达早老素-1野生型（WT）、I249 L和P433 S突变体的慢病毒感染的SH-SY 5 Y神经母细胞瘤细胞中检测这两种突变对早老素-1内蛋白水解和β-淀粉样蛋白（Aβ）产生的影响。两种突变体均显示Aβ42水平和Aβ42/Aβ40比值升高。然而，I249 L不影响早老素-1内切蛋白水解或Aβ43的产生，而P433 S突变体抑制早老素-1内切蛋白水解并增加Aβ43的产生。提示I 249和P433均通过增加Aβ42的产生和Aβ42/Aβ40的比值而对AD的早期发病起致病作用。此外，P433 S可能通过抑制PS 1内蛋白水解和促进较长Aβ肽Aβ43的产生而参与AD的极早期发病。
Clinical case study and functional characterization of the disease-associatedpresenilin-1(PSEN1) mutations may help reveal the roles ofPSEN1in the pathogenesis of Alzheimer's disease (AD). By mutation screening ofPSEN1,presenilin-2, andamyloid precursor proteingenes in two Chinese Alzheimer's pedigrees, we identified two novelPSEN1mutations,I249LandP433S. The two probands presented with progressive memory decline and subsequent psychiatric symptoms, with the age of onset at 54 and 34 years old, respectively. The effects of these two mutations on presenilin-1 endoproteolysis and β-amyloid (Aβ) production were examined in SH-SY5Y neuroblastoma cells infected with lentiviruses expressing presenilin-1 wild type (WT), I249L and P433S mutants. Both mutants showed increased Aβ42 levels and Aβ42/Aβ40 ratios. However, the I249L did not affect presenilin-1 endoproteolysis or Aβ43 production, whereas the P433S mutant inhibited presenilin-1 endoproteolysis and enhanced Aβ43 production. Our findings suggest that bothI249LandP433Sare pathogenic for early onset of AD by increasing Aβ42 production and Aβ42/Aβ40 ratios. Furthermore,P433Smay contribute to the very early onset of AD by inhibiting PS1 endoproteolysis and enhancing the production of longer Aβ peptide Aβ43.