Identification of Damaging SNPs and Their Effects on Alzheimer’s Disease-Associated PSEN1 Protein: Computational Analysis

Year 2021, Volume: 11 Issue: 2, 321 - 349, 31.12.2021

Orçun Avşar

https://doi.org/10.37094/adyujsci.884889

Abstract

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease and pathologically characterized by the presence of neurofibrillary tangles (tau aggregation) and amyloid plaques (amyloid-beta (A𝛽) aggregation). PSEN1 protein with 9 transmembrane helices acts as aspartyl protease and is one of the catalytic components of γ secretase complex, that cleaves amyloid precursor protein (APP). Furthermore, PSEN1 protein plays a significant role in the process of APP and in the generation of amyloid beta (Aβ). In the present study, it was aimed to estimate the probable deleterious effects of missense SNPs in PSEN1 gene that is associated with AD on protein stability and structure by using bioinformatics tools. SIFT, PolyPhen-2, PROVEAN, PhD-SNP, and PANTHER PSEP software were used to estimate the deleterious SNPs, whereas I-Mutant 3.0 and MUpro web tools were used to determine the effects of amino acid substitution on protein stability. Additionally, the effects of wild type and mutant amino acids on protein three-dimensional structure via modeling were predicted by Project HOPE webserver. The phylogenetic conservation of amino acid residues of PSEN1 protein was analyzed by ConSurf. In total, 386 missense SNPs were found in the human PSEN1 gene from the National Center for Biotechnology Information Single Nucleotide Polymorphism (NCBI dbSNP) database and 65 SNPs of which were determined to be deleterious or damaging. In the present study, 8 significant missense SNPs- rs63749891 (R278T), rs63750301 (P264L), rs63750353 (N135D), rs63750524 (R278S), rs63750772 (E273A), rs63751229 (P267S), rs121917807 (G266S), and rs201617677 (R157S)- were determined as high-risk pathogenic. Some differences between wild-type amino acids and mutant amino acids such as hydrophobicity, charge, size, and folding properties were determined according to the modeling findings. Our study demonstrates that high-risk pathogenic missense SNPs have the potential to alter the catalytic activity of the γ secretase complex and subsequently the amount of Aβ40 and Aβ42. Therefore, these missense SNPs may contribute to AD pathogenesis studies.

Keywords

Alzheimer’s disease, PSEN1, Gene, Mutation, SNP

Supporting Institution

None

Zarar Verici SNP’lerin ve Alzheimer Hastalığıyla İlişkili PSEN1 Proteinine Etkilerinin Tanımlanması: Hesaplamalı Analiz

Abstract

Alzheimer Hastalığı (AH), progresif nörodejeneratif hastalıktır ve patolojik olarak nörofibriler yumaklar (tau agregasyonu) ve amiloid plakların (amiloid beta (A𝛽) agregasyonu) varlığı ile karakterize edilir. 9 transmembran heliks içeren PSEN1 proteini, aspartil proteaz olarak işlev görmektedir ve amiloid öncü proteini (APP) parçalayan γ sekretaz kompleksinin katalitik bileşenlerinden biridir. Ayrıca, PSEN1 proteini APP sürecinde ve amiloid beta (A𝛽) oluşumunda önemli rol oynamaktadır. Bu çalışmada, AH ile ilişkili PSEN1 genindeki missense (yanlış anlamlı) SNP’lerin protein stabilitesi ve yapısı üzerindeki olası zararlı etkilerinin biyoinformatik araçlar kullanılarak tahmin edilmesi amaçlanmıştır. Zararlı SNP’lerin tahmin edilmesinde SIFT, PolyPhen-2, PROVEAN, PhD-SNP ve PANTHER PSEP yazılımları kullanılırken, amino asit değişiminin protein stabilitesi üzerindeki etkilerini belirlemek için I-Mutant 3.0 ve MUpro web araçları kullanıldı. Ek olarak, yabanıl tip ve mutant amino asitlerin proteinin üç boyutlu yapısı üzerindeki etkileri ise modelleme yoluyla Project HOPE programı ile tahmin edilmiştir. PSEN1 proteininin amino asit kalıntılarının filogenetik korunumu ConSurf ile analiz edildi. NCBI dbSNP veritabanında insan PSEN1 geninde toplam 386 missense SNP bulunduğu ve 65 SNP’nin ise zararlı veya zarar verici olduğu belirlendi. Bu çalışmada, 8 önemli missense SNP- rs63749891 (R278T), rs63750301 (P264L), rs63750353 (N135D), rs63750524 (R278S), rs63750772 (E273A), rs63751229 (P267S), rs121917807 (G266S), ve rs201617677 (R157S)- yüksekli riskli patojenik olarak belirlendi. Yabanıl tip ve mutant amino asitler arasındaki hidrofobiklik, yük, boyut ve katlanma özellikleri gibi bazı farklılıklar modelleme bulgularına göre belirlenmiştir. Çalışmamız, yüksek riskli patojenik missense SNP’lerin γ sekretaz kompleksinin katalitik aktivitesini ve akabinde Aβ40 ve Aβ42 miktarını değiştirme potansiyelinin olduğunu göstermektedir. Bu nedenle, bu missense SNP'ler, AH patogenez çalışmalarına katkı sağlayabilir.

Keywords

Alzheimer Hastalığı; PSEN1; Gen; Mutasyon; SNP.

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