Publication: Alzheimer Hastalığı ile İlişkilendirilen APH1A Genindeki Zararlı SNP’lerin In Silico_x000D_
Yöntemler ile Belirlenmesi
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Abstract
Alzheimer hastalığı (AH), β-amiloid (Aβ) senil plakların ve nörofibriler yumakların patolojikbirikimi ile karakterize olan ilerleyici bir nörodejeneratif hastalıktır. γ-sekretaz, AH nedeni olanamiloid β peptidi (Aβ) üretmektedir. γ-sekretaz makromoleküler bir komplekstir ve APH1A genininkodladığı protein bu komplekste yer almaktadır. Bu çalışmada, APH1A genindeki yanlış anlamlı(missense) tek nükleotid polimorfizmlerinin (SNP) proteinin yapısı ve stabilizasyonu üzerindeki olasızararlı etkilerinin in silico yöntemler kullanılarak belirlenmesi amaçlanmıştır. Zararlı SNP’lerintahmin edilmesi için PolyPhen-2 ve SIFT yazılım araçları, protein stabilizasyonu değişimlerinin tespitedilmesi için I-Mutant 2.0 yazılımı, yabanıl ve mutant tip proteinlerin üç boyutlu modellemeleri içinProject HOPE yazılım aracı kullanılmıştır. Sonuçlar, APH1A geninde yer alan toplam 3567 SNP’nin257 tanesinin yanlış anlamlı SNP olduğunu göstermiştir. 257 SNP’nin in silico analizlerine göre,rs11548266, rs74126634, rs145324799, rs199961673, rs370361277, rs370719475 ve rs376071112polimorfizmlerinin zararlı etkilerinin olabileceği belirlenmiştir. Çalışmamızda gerçekleştirdiğimiz insilico analizler, Alzheimer hastalığı ile ilgili APH1A geninde yer alan 3567 SNP’nin tamamınıngenotiplenmesi yerine proteinin yapısı ve stabilizasyonuna zararlı etkisi olabilecek SNP’leringenotiplenmesine ilişkin veri sağlamaktadır. Dolayısıyla, zararlı olduğu tespit edilen SNP’lergenotipleme çalışmalarının en önemli basamağı olan SNP seçiminde ve deney tasarımındakullanılabilecektir. Bu nedenle, elde ettiğimiz sonuçların Alzheimer hastalığı ile ilgili gelecekteyapılacak olan hem deneysel hem de in silico çalışmalara katkı sağlayacağı düşünülmektedir.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by_x000D_ pathological accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles. γ-secretase_x000D_ produces the amyloid β peptide (Aβ), which causes AD. γ-secretase is a macromolecular complex and_x000D_ the protein encoded by the APH1A gene is located in this complex. In this study, it was aimed to_x000D_ determine the possible deleterious effects of missense single nucleotide polymorphisms (SNPs) in_x000D_ APH1A gene on the protein structure and stabilization via in silico methods. PolyPhen-2 and SIFT_x000D_ were used to predict deleterious SNPs, I-Mutant 2.0 software was used to detect protein stabilization_x000D_ changes and Project HOPE software tool was used to make three-dimensional modeling of wild and_x000D_ mutant type proteins. The results showed that 257 SNPs among a total of 3567 SNPs in the APH1A_x000D_ gene were missense SNPs. According to the in silico analysis of the 257 SNPs it has been determined_x000D_ that rs11548266, rs74126634, rs145324799, rs199961673, rs370361277, rs370719475 and_x000D_ rs376071112 polymorphisms may have deleterious effects. The results of in silico analysis provide_x000D_ data for genotyping of SNPs which have deleterious effects on protein structure and stabilization_x000D_ rather than genotyping of entire 3567 SNPs in the APH1A gene associated with Alzheimer's disease._x000D_ Therefore, deleterious SNPs may be used in the selection of SNPs and experimental design which are_x000D_ the most important stages of genotyping studies. Thus, we envisaged that the obtained results will_x000D_ contribute to the further studies either experimental or in silico on Alzheimer's disease.
Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by_x000D_ pathological accumulation of β-amyloid (Aβ) senile plaques and neurofibrillary tangles. γ-secretase_x000D_ produces the amyloid β peptide (Aβ), which causes AD. γ-secretase is a macromolecular complex and_x000D_ the protein encoded by the APH1A gene is located in this complex. In this study, it was aimed to_x000D_ determine the possible deleterious effects of missense single nucleotide polymorphisms (SNPs) in_x000D_ APH1A gene on the protein structure and stabilization via in silico methods. PolyPhen-2 and SIFT_x000D_ were used to predict deleterious SNPs, I-Mutant 2.0 software was used to detect protein stabilization_x000D_ changes and Project HOPE software tool was used to make three-dimensional modeling of wild and_x000D_ mutant type proteins. The results showed that 257 SNPs among a total of 3567 SNPs in the APH1A_x000D_ gene were missense SNPs. According to the in silico analysis of the 257 SNPs it has been determined_x000D_ that rs11548266, rs74126634, rs145324799, rs199961673, rs370361277, rs370719475 and_x000D_ rs376071112 polymorphisms may have deleterious effects. The results of in silico analysis provide_x000D_ data for genotyping of SNPs which have deleterious effects on protein structure and stabilization_x000D_ rather than genotyping of entire 3567 SNPs in the APH1A gene associated with Alzheimer's disease._x000D_ Therefore, deleterious SNPs may be used in the selection of SNPs and experimental design which are_x000D_ the most important stages of genotyping studies. Thus, we envisaged that the obtained results will_x000D_ contribute to the further studies either experimental or in silico on Alzheimer's disease.