与阿尔茨海默病相关的血管紧张素转换酶 (ACE) 基因突变对血液 ACE 表型的影响。

IF 3.9 3区 工程技术 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Olga V Kryukova, Igor O Islanov, Elena V Zaklyazminskaya, Dmitry O Korostin, Vera A Belova, Valery V Cheranev, Zhanna A Repinskaia, Svetlana A Tonevitskaya, Pavel A Petukhov, Steven M Dudek, Olga A Kost, Denis V Rebrikov, Sergei M Danilov
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引用次数: 0

摘要

背景:我们最近对现有的 1200 多种错义 ACE 基因突变进行了分析,发现有 400 多种基因突变具有损伤性,因此我们推测杂合功能缺失 (LoF) ACE 基因突变(导致低 ACE 水平)携带者可能有罹患晚发性阿尔茨海默病(AD)的风险。方法:在此,我们对 41 名患有 10 种不同杂合性 ACE 突变的受试者以及 33 名对照者的 EDTA 血浆中的 ACE 水平进行了量化,并使用一组针对 ACE 和两种 ACE 底物的 mAbs 估计了这些突变对 ACE 表型的影响:我们发现,AD 相关 ACE N 结构域中相对常见(约 1%)的 ACE 突变 Y215C 和 G325R 是真正的损伤性突变,很可能存在转运缺陷,血浆中的 ACE 水平仅为对照组的约 50%。另一个与AD相关的ACE突变R1250Q位于细胞质尾部,但并没有导致ACE的减少,也很可能不影响表面ACE的表达。我们还开发了一种方法来识别 N 结构域中存在反催化突变的患者。这些突变可能导致淀粉样 beta 肽 Aβ42 的降解减少,而 Aβ42 是淀粉样沉积的重要组成部分。因此,这些突变可能会成为AD发病的风险因素:因此,对所有 ACE 基因突变患者的血液 ACE 水平进行系统分析,有可能识别出晚期 AD 风险增加的个体。这些人可能会受益于未来的预防或治疗干预措施,其中包括化学和药理伴侣以及蛋白酶体抑制剂的组合,目的是增强 ACE 蛋白的运输。此前,我们已在转运缺陷 ACE 突变 Q1069R 的细胞模型中证实了这种方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Effects of Angiotensin-I-Converting Enzyme (ACE) Mutations Associated with Alzheimer's Disease on Blood ACE Phenotype.

Backgrounds: Our recent analysis of 1200+ existing missense ACE mutations revealed that 400+ mutations are damaging and led us to hypothesize that carriers of heterozygous loss-of-function (LoF) ACE mutations (which result in low ACE levels) could be at risk for the development of late-onset Alzheimer's disease (AD).

Methods: Here, we quantified blood ACE levels in EDTA plasma from 41 subjects with 10 different heterozygous ACE mutations, as well as 33 controls, and estimated the effect of these mutations on ACE phenotype using a set of mAbs to ACE and two ACE substrates.

Results: We found that relatively frequent (~1%) AD-associated ACE mutations in the N domain of ACE, Y215C, and G325R are truly damaging and likely transport-deficient, with the ACE levels in plasma at only ~50% of controls. Another AD-associated ACE mutation, R1250Q, in the cytoplasmic tail, did not cause a decrease in ACE and likely did not affect surface ACE expression. We have also developed a method to identify patients with anti-catalytic mutations in the N domain. These mutations may result in reduced degradation of amyloid beta peptide Aβ42, an important component for amyloid deposition. Consequently, these could pose a risk factor for the development of AD.

Conclusions: Therefore, a systematic analysis of blood ACE levels in patients with all ACE mutations has the potential to identify individuals at an increased risk of late-onset AD. These individuals may benefit from future preventive or therapeutic interventions involving a combination of chemical and pharmacological chaperones, as well as proteasome inhibitors, aiming to enhance ACE protein traffic. This approach has been previously demonstrated in our cell model of the transport-deficient ACE mutation Q1069R.

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来源期刊
Biomedicines
Biomedicines Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology
CiteScore
5.20
自引率
8.50%
发文量
2823
审稿时长
8 weeks
期刊介绍: Biomedicines (ISSN 2227-9059; CODEN: BIOMID) is an international, scientific, open access journal on biomedicines published quarterly online by MDPI.
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