Jeppesen Brian, Costello Laura, Fung Adam, Stanley Erin, McDonald Jessica, Lambert Abbie, Johnson Bennett, Gentile Lisa
Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA.
Biochem Biophys Res Commun. 2007 Apr 13;355(3):820-4. doi: 10.1016/j.bbrc.2007.02.033. Epub 2007 Feb 15.
Since its cloning in 1995, missense point mutations in presenilin I (PS-I) have been shown to be responsible for greater than 70% of the cases of early onset familial Alzheimer's disease (EOFAD), which can affect individuals as early as age 18. PS-I is known to be a component of gamma-secretase, the enzyme responsible for cleavage of the amyloid precursor protein (APP) into 42 amino acid peptides that aggregate to form the plaques surrounding neurons of Alzheimer's patients. It has recently been hypothesized that wild-type (wt) PS-I contains an autoinhibitory module that prevents gamma-secretase cleavage of the APP, while pathogenic PS-I point mutants lack a structure necessary for this inhibition. In this work, spectroscopic data is presented that does not correlate structure or stability of the proposed PS-I autoinhibitory module with pathogenicity.
自1995年被克隆以来，早老素I（PS-I）中的错义点突变已被证明与超过70%的早发性家族性阿尔茨海默病（EOFAD）病例有关，这种疾病最早可在18岁时影响个体。已知PS-I是γ-分泌酶的一个组成部分，该酶负责将淀粉样前体蛋白（APP）切割成42个氨基酸的肽段，这些肽段聚集形成阿尔茨海默病患者神经元周围的斑块。最近有人提出假说，野生型（wt）PS-I含有一个自抑制模块，可阻止γ-分泌酶对APP的切割，而致病性PS-I点突变体则缺乏这种抑制所需的结构。在这项工作中，所呈现的光谱数据并未将所提出的PS-I自抑制模块的结构或稳定性与致病性联系起来。
