College of Life Sciences, Anhui Normal University, Wuhu, 241002, Anhui, China.
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, and KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650223, Yunnan, China.
Mol Neurobiol. 2021 May;58(5):1894-1903. doi: 10.1007/s12035-020-02271-z. Epub 2021 Jan 6.
Accumulating evidence demonstrated that GABAergic dysfunction contributes to the pathogenesis of Alzheimer's disease (AD). The GABA aminotransferase (ABAT) gene encodes a mitochondrial GABA transaminase and plays key roles in the biogenesis and metabolism of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter. In this study, we performed an integrative study at the genetic and expression levels to investigate the potential genetic association between the ABAT gene and AD. Through re-analyzing data from the currently largest meta-analysis of AD genome-wide association study (GWAS), we identified genetic variants in the 3'-UTR of ABAT as the top AD-associated SNPs (P < 1 × 10) in this gene. Functional annotation of these AD-associated SNPs indicated that these SNPs are located in the regulatory regions of transcription factors or/and microRNAs. Expression quantitative trait loci (eQTL) analysis and luciferase reporter assay showed that the AD risk alleles of these SNPs were associated with a reduced expression level of ABAT. Further analysis of mRNA expression data and single-cell transcriptome data of AD patients showed that ABAT reduction in the neuron is an early event during AD development. Overall, our results indicated that ABAT genetic variants may be associated with AD through affecting its mRNA expression. An abnormal level of ABAT will lead to a disturbance of the GABAergic signal pathway in AD brains.
越来越多的证据表明，GABA 能神经功能障碍与阿尔茨海默病（AD）的发病机制有关。GABA 转氨酶（ABAT）基因编码一种线粒体 GABA 转氨酶，在γ-氨基丁酸（GABA）的生物发生和代谢中发挥关键作用，GABA 是一种主要的抑制性神经递质。在这项研究中，我们在遗传和表达水平上进行了综合研究，以研究 ABAT 基因与 AD 之间的潜在遗传关联。通过重新分析目前最大的 AD 全基因组关联研究（GWAS）的荟萃分析数据，我们确定了 ABAT 基因 3'-UTR 中的遗传变异是该基因中与 AD 关联最显著的 SNPs（P<1×10）。这些与 AD 相关的 SNPs 的功能注释表明，这些 SNPs 位于转录因子或/和 microRNAs 的调控区域。表达数量性状基因座（eQTL）分析和荧光素酶报告基因检测表明，这些 SNPs 的 AD 风险等位基因与 ABAT 表达水平降低有关。对 AD 患者的 mRNA 表达数据和单细胞转录组数据的进一步分析表明，ABAT 在神经元中的减少是 AD 发展过程中的早期事件。总的来说，我们的结果表明，ABAT 遗传变异可能通过影响其 mRNA 表达与 AD 相关。ABAT 水平异常会导致 AD 大脑中 GABA 能信号通路的紊乱。
