Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function.
Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function.
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DOI：
10.1186/1750-1326-6-70
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发表时间：
2011-10-07
影响因子：
15.1
通讯作者：
Hébert SS
中科院分区：
文献类型：
--
作者：
Delay C;Calon F;Mathews P;Hébert SS
APP 表达失调可导致遗传性阿尔茨海默病 (AD)。最近的证据支持这样的假设：位于 microRNA (miRNA) 靶位点的多态性可能会影响患帕金森病 (PD) 和额颞叶痴呆等神经退行性疾病的风险。近年来，在有痴呆家族史的AD患者中发现了多个位于APP 3'UTR的单核苷酸多态性（SNP）。由于 miRNA 先前已被认为与 APP 表达调控有关，因此我们着手确定这些多态性是否会影响 miRNA 功能，从而影响 APP 水平。生物信息学分析确定了 12 个假定的 miRNA 结合位点，位于 APP 3'UTR 变体 T117C、A454G 和 A833C 中或附近。在这些候选miRNA中，包括miR-20a、miR-17、miR-147、miR-655、miR-323-3p、miR-644和miR-153在内的7种miRNA可以在体外和细胞生理条件下调节APP表达。使用基于荧光素酶的检测，我们可以证明 T117C 变体抑制 miR-147 结合，而 A454G 变体增加 miR-20a 结合，因此对 APP 表达产生相反的影响。总而言之，我们的结果提供了原理证明，即 APP 3'UTR 多态性可以通过调节 APP 表达调节来影响 AD 风险，并为遗传性和散发性 AD 的进一步关联研究奠定了基础。
APP expression misregulation can cause genetic Alzheimer's disease (AD). Recent evidences support the hypothesis that polymorphisms located in microRNA (miRNA) target sites could influence the risk of developing neurodegenerative disorders such as Parkinson's disease (PD) and frontotemporal dementia. Recently, a number of single nucleotide polymorphisms (SNPs) located in the 3'UTR of APP have been found in AD patients with family history of dementia. Because miRNAs have previously been implicated in APP expression regulation, we set out to determine whether these polymorphisms could affect miRNA function and therefore APP levels. Bioinformatics analysis identified twelve putative miRNA bindings sites located in or near the APP 3'UTR variants T117C, A454G and A833C. Among those candidates, seven miRNAs, including miR-20a, miR-17, miR-147, miR-655, miR-323-3p, miR-644, and miR-153 could regulate APP expression in vitro and under physiological conditions in cells. Using luciferase-based assays, we could show that the T117C variant inhibited miR-147 binding, whereas the A454G variant increased miR-20a binding, consequently having opposite effects on APP expression. Taken together, our results provide proof-of-principle that APP 3'UTR polymorphisms could affect AD risk through modulation of APP expression regulation, and set the stage for further association studies in genetic and sporadic AD.
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DOI：
10.1073/pnas.0710263105
发表时间：
2008-04-29
影响因子：
11.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart
影响因子：
3.9
作者：
Bettens, Karolien;Brouwers, Nathalie;Van Broeckhoven, Christine
通讯作者：
Van Broeckhoven, Christine
Mirbase：MicroRNA基因组学的工具。
影响因子：
14.9
作者：
Griffiths-Jones, Sam;Saini, Harpreet Kaur;van Dongen, Stijn;Enright, Anton J.
通讯作者：
Enright, Anton J.
影响因子：
3.7
作者：
Nunez-Iglesias J;Liu CC;Morgan TE;Finch CE;Zhou XJ
通讯作者：
Zhou XJ
影响因子：
6.1
作者：
Hebert, Sebastien S.;Horre, Katrien;De Strooper, Bart
通讯作者：
De Strooper, Bart