Elsworthy Richard J, Pearce Alex, Masoudzadeh Farnoush, Koska Klaudia, Lodhiya Honey, Meher Gargi, Adjej Jodelle, Brookes Keeley J
School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham B15 2TT, UK.
Department of Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham NG11 8NF, UK.
Int J Mol Sci. 2025 Jan 9;26(2):524. doi: 10.3390/ijms26020524.
The immune system and neuroinflammation are now well established in the aetiology of neurodegeneration. Previous studies of transcriptomic and gene association studies have highlighted the potential of the 2'-5' oligoadenylate synthetase 1 (OAS1) to play a role in Alzheimer's disease. OAS1 is a viral response gene, interferon-induced, dsRNA activated enzyme, which binds RNase L to degrade dsRNA, and has been associated with COVID-19 response. This study explores whether a viral defence gene could play a vital role in neurodegeneration pathology. The genotyping of five SNPs across the locus was conducted in the Brains for Dementia Research (BDR) Cohort for association with AD. RNA-sequencing data were explored for differences in gene expression between phenotypes and genotypes. Finally, levels of dsRNA were measured in control cell lines, prior to and after exposure to amyloid oligomers and in cells harbouring a dementia-relevant mutation. No association of any of the SNPs investigated were associated with the AD phenotype in the BDR cohort. However, gene expression data supported the previous observation that the minor allele haplotype was associated with higher levels of the gene expression and the presence of an alternative transcript. Further to this, the presence of endogenous dsRNA was found to increase with exposure to amyloid oligomers and in the cell line with a dementia-relevant mutation. The data presented here suggest further exploration of the gene in relation to dementia is warranted. Investigations of whether carriers of the protective haplotype lower dsRNA presence and in turn lower inflammation and cell death are required to support the role of the gene as a moderator of neurodegeneration.
免疫系统和神经炎症在神经退行性疾病的病因学中已得到充分证实。先前的转录组学和基因关联研究突出了2'-5'寡腺苷酸合成酶1（OAS1）在阿尔茨海默病中发挥作用的潜力。OAS1是一种病毒反应基因，由干扰素诱导、双链RNA激活的酶，它与核糖核酸酶L结合以降解双链RNA，并与COVID-19反应相关。本研究探讨了一种病毒防御基因是否可能在神经退行性疾病病理学中发挥关键作用。在痴呆症研究大脑（BDR）队列中对该基因座上的五个单核苷酸多态性（SNP）进行基因分型，以研究其与阿尔茨海默病的关联。探索RNA测序数据以了解不同表型和基因型之间基因表达的差异。最后，在对照细胞系中测量双链RNA水平，在暴露于淀粉样寡聚体之前和之后以及在携带与痴呆相关突变的细胞中进行测量。在BDR队列中，所研究的任何一个SNP均与阿尔茨海默病表型无关联。然而，基因表达数据支持了先前的观察结果，即次要等位基因单倍型与该基因的较高表达水平和一种替代转录本的存在相关。除此之外，发现内源性双链RNA的存在随着暴露于淀粉样寡聚体以及在具有与痴呆相关突变的细胞系中而增加。此处呈现的数据表明有必要进一步探索该基因与痴呆症的关系。需要研究保护性单倍型的携带者是否降低双链RNA的存在，进而降低炎症和细胞死亡，以支持该基因作为神经退行性疾病调节因子的作用。
