Albayrak İrem Gülfem, Atasever Arslan Belkıs
Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Üsküdar University, Istanbul, Turkey.
Toxicol Rep. 2025 May 28;14:102060. doi: 10.1016/j.toxrep.2025.102060. eCollection 2025 Jun.
Glycogen synthase kinase-3 beta (GSK-3β) is well recognized for its role in diverse physiological processes, including apoptosis, mitochondrial function, and gene transcription regulation. The precise regulation of GSK-3β activity is critical for maintaining neuronal health, and dysregulation may result in disturbances in neurological functions. Polymorphisms in the GSK-3β gene may increase susceptibility to neurodegenerative disorders. To assess the structural and functional consequences of deleterious SNPs in GSK-3β, various in silico approaches was utilized. Analysis identified 27 deleterious SNPs in the GSK-3β gene, among which 10 were classified as damaging by SIFT, PolyPhen-2, and MutPred2. The Project Hope software simulated ten harmful mutations in the GSK-3β gene. The pathways associated with neurodegeneration involving the GSK-3β gene and its interacting genes were identified through the KEGG and GeneMANIA databases, respectively. The V317F mutation was shown to reduce GSK-3β inhibition by highly selective inhibitory ligand PF04802367 (PF-367) and impair the GSK-3β-Tau interaction. The influence of GSK3β on Aβ formation suggests that the V317F mutation has a tau-independent neurodegenerative impact. The experimental investigation of the V317F mutant GSK-3β's effect on neurodegeneration may enhance the understanding of the biomarker potential of rs140668532 in Alzheimer's disease.
糖原合酶激酶-3β（GSK-3β）因其在多种生理过程中的作用而广为人知，这些生理过程包括细胞凋亡、线粒体功能以及基因转录调控。GSK-3β活性的精确调控对于维持神经元健康至关重要，而调控异常可能导致神经功能紊乱。GSK-3β基因的多态性可能会增加患神经退行性疾病的易感性。为了评估GSK-3β中有害单核苷酸多态性（SNP）的结构和功能后果，研究人员采用了多种计算机模拟方法。分析确定了GSK-3β基因中的27个有害SNP，其中10个被SIFT、PolyPhen-2和MutPred2分类为有害突变。希望工程软件模拟了GSK-3β基因中的10种有害突变。分别通过KEGG和GeneMANIA数据库确定了与涉及GSK-3β基因及其相互作用基因的神经退行性变相关的信号通路。V317F突变被证明会降低高选择性抑制性配体PF04802367（PF-367）对GSK-3β的抑制作用，并损害GSK-3β与tau蛋白的相互作用。GSK3β对淀粉样蛋白β（Aβ）形成的影响表明，V317F突变具有不依赖tau蛋白的神经退行性影响。对V317F突变型GSK-3β对神经退行性变影响的实验研究可能会增进对阿尔茨海默病中rs140668532作为生物标志物潜力的理解。
