In silico analysis of single nucleotide polymorphisms in the coding regions of the genes associated with the amyloidogenic pathway

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid beta (Aβ) peptide and hyperphosphorilated tau proteins in the brain, leading to synaptic dysfunction and neuronal loss. Aβ is produced through the proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE1) and the γ-secretase complex (PSEN1, PSEN2, PSENEN, APH1A/B, and NCSTN), a mechanism referred to as the amyloidogenic pathway. Numerous studies have demonstrated that certain coding variants in APP, BACE1, and γ-secretase complex genes play a critical role in the genetic background of AD, particularly in early-onset forms. In this thesis, the potential molecular impacts of missense single nucleotide polymorphisms (SNPs) located in the coding regions of APP, BACE1, PSEN1, PSEN2, PSENEN, APH1, and NCSTN were systematically evaluated using Phyre2, Robetta SIFT, PolyPhen-2, PANTHER, SNPs&GO, Meta-SNP, PredictSNP1, PredictSNP2 PhD-SNPg, CADD, FATHMM-XF, MutPred2, DynaMut2, mCSM-Membrane, INPS-MD, ConSurf, HOPE and Missense3D in silico tools. Through this comprehensive approach, the potential effects of each variant on protein structural integrity, functional properties, and evolutionary conservation were assessed. As a result, the following variants were predicted to be deleterious: G120D, C158Y, P173H, C291F, C316R, G323R, G323V, G325V, G326V, C337R, R527G, L548P and G709S in APP; Y75C, Y75H, G135D, G178R, G238A, G238R, G239V, Y259D, C330R, L346P, Y366H and R412P in BACE1; G78R, I140N, L153P, Y154C, L174R, F205S, L226R, K239E, L268R, L286P, L381H, F388S, L424R, and F447S in PSEN1; G84E, Y160C, Y294D, and Y294H in PSEN2; G22E and L26P in PSENEN; G122V, G122D, G126D, G126S, and A161D in APH1A; L72P, L116R, A160P, T163K, and L169R in APH1B; and R52H, L282P, G294E, and G332R in NCSTN. The findings are expected to guide future experimental validation studies and contribute to a better understanding of AD pathogenesis.