{"title":"GSK-3β基因rs140668532 SNP作为阿尔茨海默病的潜在生物标志物:来自计算模型的见解","authors":"İrem Gülfem Albayrak, Belkıs Atasever Arslan","doi":"10.1016/j.toxrep.2025.102060","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":23129,"journal":{"name":"Toxicology Reports","volume":"14 ","pages":"102060"},"PeriodicalIF":0.0000,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163410/pdf/","citationCount":"0","resultStr":"{\"title\":\"The rs140668532 SNP in GSK-3β gene as a potential biomarker for Alzheimer's disease: Insights from computational modeling.\",\"authors\":\"İrem Gülfem Albayrak, Belkıs Atasever Arslan\",\"doi\":\"10.1016/j.toxrep.2025.102060\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":23129,\"journal\":{\"name\":\"Toxicology Reports\",\"volume\":\"14 \",\"pages\":\"102060\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163410/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology Reports\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.toxrep.2025.102060\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/6/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"Environmental Science\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology Reports","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.toxrep.2025.102060","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/6/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"Environmental Science","Score":null,"Total":0}
The rs140668532 SNP in GSK-3β gene as a potential biomarker for Alzheimer's disease: Insights from computational modeling.
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.