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阿尔茨海默病中的 Sirtuins：SIRT2 相关的基因表型及其对药物表观遗传学的影响。

Sirtuins in Alzheimer's Disease: SIRT2-Related GenoPhenotypes and Implications for PharmacoEpiGenetics.

机构信息

EuroEspes Biomedical Research Center, Institute of Medical Science and Genomic Medicine, 15165 Bergondo, Corunna, Spain.

Department of Psychiatry and Behavioral Science, Stony Brook University, Stony Brook, NY 11794, USA.

出版信息

Int J Mol Sci. 2019 Mar 12;20(5):1249. doi: 10.3390/ijms20051249.

DOI:10.3390/ijms20051249
PMID:30871086
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6429449/
Abstract

Sirtuins (SIRT1-7) are NAD⁺-dependent protein deacetylases/ADP ribosyltransferases with important roles in chromatin silencing, cell cycle regulation, cellular differentiation, cellular stress response, metabolism and aging. Sirtuins are components of the epigenetic machinery, which is disturbed in Alzheimer's disease (AD), contributing to AD pathogenesis. There is an association between the genotype (rs10410544) (50.92%) and AD susceptibility in the -negative population (, 34.72%; 14.36%). The integration of and variants in bigenic clusters yields 18 haplotypes. The 5 most frequent bigenic genotypes in AD are (27.81%), (21.36%), (15.29%), (9.76%) and (7.18%). There is an accumulation of and carriers in > > carriers, and also of and carriers in patients who harbor the genotype. variants influence biochemical, hematological, metabolic and cardiovascular phenotypes, and modestly affect the pharmacoepigenetic outcome in AD. carriers are the best responders, carriers show an intermediate pattern, and carriers are the worst responders to a multifactorial treatment. In bigenic clusters, carriers respond better than and carriers, whereas and carriers behave as the worst responders. CYP2D6 extensive metabolizers (EM) are the best responders, poor metabolizers (PM) are the worst responders, and ultra-rapid metabolizers (UM) tend to be better responders that intermediate metabolizers (IM). In association with genophenotypes, -EMs are the best responders. Some Sirtuin modulators might be potential candidates for AD treatment.

摘要

去乙酰化酶/ADP 核糖基转移酶（Sirtuins）家族（SIRT1-7）是 NAD+依赖的蛋白去乙酰化酶/ADP 核糖基转移酶，在染色质沉默、细胞周期调控、细胞分化、细胞应激反应、代谢和衰老等过程中发挥重要作用。Sirtuins 是表观遗传机制的组成部分，在阿尔茨海默病（AD）中受到干扰，导致 AD 发病机制。在-阴性人群中，与 AD 易感性相关的 基因型（rs10410544）（50.92%）和 AD 易感性相关（，34.72%；14.36%）。在双基因簇中整合和变体产生 18 种单倍型。AD 中最常见的 5 种双基因基因型是（27.81%）、（21.36%）、（15.29%）、（9.76%）和（7.18%）。在> > 携带者中积累了和携带者，也在携带基因型的患者中积累了和携带者。变体影响生化、血液学、代谢和心血管表型，适度影响 AD 的药物表观遗传学结果。携带者是最佳反应者，携带者表现为中间模式，而携带者是对多因素治疗反应最差的。在双基因簇中，携带者比和携带者反应更好，而和携带者表现为最差反应者。CYP2D6 广泛代谢者（EM）是最佳反应者，弱代谢者（PM）是最差反应者，超快代谢者（UM）倾向于比中间代谢者（IM）更好的反应者。与 genophenotypes 相关联，-EMs 是最佳反应者。一些 Sirtuin 调节剂可能是 AD 治疗的潜在候选药物。

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