# The rs140668532 SNP in GSK-3β gene as a potential biomarker for Alzheimer’s disease: Insights from computational modeling

## TL;DR

This study identifies the rs140668532 SNP in the GSK-3β gene as a potential biomarker for Alzheimer’s disease using computational modeling.

## Contribution

The study reveals that the rs140668532 SNP reduces GSK-3β inhibition and weakens its interaction with Tau, suggesting a new biomarker for Alzheimer’s disease.

## Key findings

- Twenty-seven deleterious SNPs were identified in the GSK-3β gene.
- The rs140668532 SNP weakens GSK-3β inhibition and its interaction with Tau protein.
- The rs140668532 SNP may serve as a potential biomarker for Alzheimer’s disease.

## Abstract

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.

•Twenty-seven deleterious SNPs have been identified in the GSK-3β gene.•Numerous in silico approaches have been applied to analyze the effects of these SNPs.•rs140668532 reduced GSK-3β inhibition and weakened its interaction with Tau protein.•The rs140668532 SNP may be a potential biomarker in Alzheimer's disease.

Twenty-seven deleterious SNPs have been identified in the GSK-3β gene.

Numerous in silico approaches have been applied to analyze the effects of these SNPs.

rs140668532 reduced GSK-3β inhibition and weakened its interaction with Tau protein.

The rs140668532 SNP may be a potential biomarker in Alzheimer's disease.