中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (11): 2452-2458.doi: 10.4103/1673-5374.339004

• 原著:退行性病与再生 • 上一篇    下一篇

谷胱甘肽 S-转移酶 omega-1 的遗传解剖：新下游靶点和阿尔茨海默病通路鉴定

  

  • 出版日期:2022-11-15 发布日期:2022-04-22
  • 基金资助:
    国家自然科学基金项目（81200828，32070998），江苏省重点研发计划(社会发展)（BE2020667），江苏省“333工程高层次人才”项目（BRA2020076），江苏省高等学校优先学术发展项目

Genetic dissection of glutathione S-transferase omega-1: identification of novel downstream targets and Alzheimer’s disease pathways

Yue Jia1, #, Meng-Die Gao2, #, Yun-Fang Liu1, Lu Lu3, Gang Chen1, 2, 4, *, Ying Chen1, 4, *   

  1. 1Department of Histology and Embryology, Medical College, Nantong University, Nantong, Jiangsu Province, China; 2Key Laboratory of Neuroregeneration of Jiangsu and the Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 3Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN, USA; 4Department of Anesthesiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
  • Online:2022-11-15 Published:2022-04-22
  • Contact: Ying Chen, PhD, yingchen@ntu.edu.cn; Gang Chen, PhD, chengang6626@ntu.edu.cn.
  • Supported by:
    This study was supported by the Natural Science Foundation of China, Nos. 81200828 (to YC), 32070998 (to GC), the Key Research and Development Program (Social Development) of Jiangsu Province, No. BE2020667 (to GC), the Foundation of Jiangsu Province “333 Project High-level Talents”, No. BRA2020076 (to GC), and the Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD).

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摘要：

阿尔茨海默病受到遗传因素的影响。既往研究发现，谷胱甘肽 S-转移酶 omega-1基因多态性已被证实是阿尔茨海默病的遗传危险因素。实验通过遗传基因组学手段，借助BXD重组近交系小鼠海马组织的基因表达和基因型资料，解析了谷胱甘肽S-转移酶omega-1基因的表达调控，探寻了谷胱甘肽S-转移酶omega-1相关的阿尔茨海默病候选基因。结果发现，（1）在BXD 重组近交系小鼠海马组织中谷胱甘肽S-转移酶omega-1是受顺式调节基因座调控基因的控制。谷胱甘肽S-转移酶omega-1基因表达水平与尾壳核中的胶质酸性纤维蛋白水平、皮质灰质体积和海马苔藓纤维通路体积等中枢神经系统表型有关。（2）全基因组关联分析结果显示有2168种基因与谷胱甘肽S-转移酶omega-1存在较高相关性，且部分基因同时参与神经退行性疾病相关的重要生物学进程，其中部分谷胱甘肽S-转移酶omega-1的相关基因已被证实为阿尔茨海默病的易感基因，如APP、Grin2b、Ide和Psenen等。（3）为评估Gsto1和候选下游网络靶点的关系，进一步以Gsto1小干扰RNA转染星形胶质细胞，结果确认对Pa2g4的表达产生了影响。（4）结果表明Pa2g4可能是Gsto1的下游靶点，且谷胱甘肽S-转移酶omega-1很可能协同了这部分高相关基因和下游候选基因共同参与了阿尔茨海默病发生。

https://orcid.org/0000-0003-2363-0550 (Ying Chen); https://orcid.org/0000-0003-3669-5687 (Gang Chen)

关键词: 谷胱甘肽S-转移酶Omega-1, Pa2g4, 阿尔茨海默病, BXD重组近交系小鼠, 遗传基因组学, 数量性状基因座, 相关分析, 表达变异, 共表达, 海马

Abstract: Alzheimer’s disease (AD) is affected by genetic factors. Polymorphisms in the glutathione S-transferase omega-1 (Gsto1) gene have been shown by genetic correlation analyses performed in different ethnic populations to be genetic risk factors for AD. Gene expression profile data from BXD recombinant inbred mice were used in combination with genetic and bioinformatic analyses to characterize the mechanisms underlying regulation of Gsto1 variation regulation and to identify network members that may contribute to AD risk or progression. Allele-specific assays confirmed that variation in Gsto1 expression is controlled by cis-expression quantitative trait loci. We found that Gsto1 mRNA levels were related to several central nervous system traits, such as glial acidic fibrillary protein levels in the caudate putamen, cortical gray matter volume, and hippocampus mossy fiber pathway volume. We identified 2168 genes whose expression was highly correlated with that of Gsto1. Some genes were enriched for the most common neurodegenerative diseases. Some Gsto1-related genes identified in this study had previously been identified as susceptibility genes for AD, such as APP, Grin2b, Ide, and Psenen. To evaluate the relationships between Gsto1 and candidate network members, we transfected astrocytes with Gsto1 siRNA and assessed the effect on putative downstream effectors. We confirmed that knockdown of Gsto1 had a significant influence on Pa2g4 expression, suggesting that Pa2g4 may be a downstream effector of Gsto1, and that both genes interact with other genes in a network during AD pathogenesis.

Key words: Alzheimer’s disease, BXD recombinant inbred mice, co-expression, correlation analysis, expression quantitative trait locus, expression variation, genetic dissection, glutathione S-transferase omega-1, hippocampus, proliferation-associated 2G4