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A Presenilin-1 Mutation Identified in Familial Alzheimer Disease with Cotton Wool Plaques Causes a Nearly Complete Loss of γ-Secretase Activity*

机译:在家族性阿尔茨海默氏病中发现的Presenilin-1突变与棉签导致γ-分泌酶活性几乎完全丧失*

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摘要

Mutations in presenilin-1 and presenilin-2 (PS1 and PS2) are the most common cause of familial Alzheimer disease. PS1 and PS2 are the presumptive catalytic components of the multisubunit γ-secretase complex, which proteolyzes a number of type I transmembrane proteins, including the amyloid precursor protein (APP) and Notch. APP processing by γ-secretase produces β-amyloid peptides (Aβ40 and Aβ42) that accumulate in the Alzheimer disease brain. Here we identify a pathogenic L435F mutation in PS1 in two affected siblings with early-onset familial Alzheimer disease characterized by deposition of cerebral cotton wool plaques. The L435F mutation resides in a conserved C-terminal PAL sequence implicated in active site conformation and catalytic activity. The impact of PS1 mutations in and around the PAL motif on γ-secretase activity was assessed by expression of mutant PS1 in mouse embryo fibroblasts lacking endogenous PS1 and PS2. Surprisingly, the L435F mutation caused a nearly complete loss of γ-secretase activity, including >90% reductions in the generation of Aβ40, Aβ42, and the APP and Notch intracellular domains. Two nonpathogenic PS1 mutations, P433L and L435R, caused essentially complete loss of γ-secretase activity, whereas two previously identified pathogenic PS1 mutations, P436Q and P436S, caused partial loss of function with substantial reductions in production of Aβ40, Aβ42, and the APP and Notch intracellular domains. These results argue against overproduction of Aβ42 as an essential property of presenilin proteins bearing pathogenic mutations. Rather, our findings provide support for the hypothesis that pathogenic mutations cause a general loss of presenilin function.
机译:presenilin-1和presenilin-2(PS1和PS2)的突变是家族性阿尔茨海默氏病的最常见原因。 PS1和PS2是多亚基γ-分泌酶复合物的推定催化成分,该复合物蛋白水解许多I型跨膜蛋白,包括淀粉样前体蛋白(APP)和Notch。 γ-分泌酶对APP进行处理后会产生在Alzheimer病大脑中积累的β-淀粉样肽(Aβ40和Aβ42)。在这里,我们在两个受影响的兄弟姐妹中发现了PS1中的致病性L435F突变,这些兄弟姐妹患有以脑棉斑块沉积为特征的早发家族性阿尔茨海默病。 L435F突变位于保守的C末端PAL序列中,涉及活性位点构象和催化活性。通过在缺乏内源性PS1和PS2的小鼠胚胎成纤维细胞中突变PS1的表达来评估PAL基序及其周围PS1突变对γ分泌酶活性的影响。令人惊讶的是,L435F突变导致γ分泌酶活性几乎完全丧失,包括Aβ40,Aβ42以及APP和Notch细胞内结构域的生成减少了90%以上。两个非致病性PS1突变P433L和L435R导致γ分泌酶活性基本上完全丧失,而两个先前确定的致病PS1突变P436Q和P436S导致部分功能丧失,导致Aβ40,Aβ42和APP的产生大量减少。缺口细胞内结构域。这些结果反对Aβ42的过量生产是具有致病性突变的早老素蛋白的基本特性。相反,我们的发现为病原性突变导致早老素功能普遍丧失的假设提供了支持。

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