Department of Genetics and Bioengineering, International University of Sarajevo, Sarajevo, Bosnia and Herzegovina.
Hamidiye Faculty of Medicine, Program of Medical Biology, University of Health Sciences, İstanbul, Türkiye.
Neurogenetics. 2024 Nov 26;26(1):8. doi: 10.1007/s10048-024-00786-4.
Alzheimer's disease (AD) is a neurodegenerative disorder that is presented with a progressive loss of memory, a decline in cognitive abilities and multiple changes in behavior. Its pathogenicity has been linked to genetic factors in approximately 60-80% of the cases specifically APOE gene family and as well as other gene families. This study utilized advanced computational biology methods to analyze AD-associated nsSNPs extracted from the NHGRI-EBI GWAS Catalog. Ensembl Variant Effect Predictor (VEP) is used to annotate the variants associated with AD. Annotated missense variants were subjected to PolyPhen-2, SNPs&Go, PredictSNP servers which were used to predict pathogenicity of selected missense variants by protein sequence information. DynaMut and DUET servers were applied to determine protein stability due to the amino acid change by integrating protein structure information. Missense variations associated with AD were annotated to 26 proteins and further analyzed in our study. Following rigorous data filtration steps, 15 candidate variants (13 proteins) were identified and subjected to sequence and structure-based analysis. Finally in this in-silico study, five deleterious non-synonymous single nucleotide polymorphisms (nsSNPs) were identified in ACKR2(V41A), APOE(R176C), ATP8B4(G395S), LAMB2(E987K), and TOMM40(R239W), and these findings were subsequently backed-up by existing in-vivo and in-vitro literature. This study not only provides invaluable insight into the intricate pathogenic mechanisms underlying AD but also offers a distinctive perspective that paves the way for future, more comprehensive investigations aimed at unraveling the molecular intricacies responsible for the development and progression of AD. Nonetheless, it is imperative that further rigorous in vivo and in vitro experiments are conducted to validate and expand upon the findings presented here.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是进行性记忆丧失、认知能力下降和行为的多种变化。其致病性已与大约 60-80%的病例中的遗传因素相关，特别是 APOE 基因家族以及其他基因家族。本研究利用先进的计算生物学方法分析了从 NHGRI-EBI GWAS 目录中提取的与 AD 相关的 nsSNPs。Ensembl Variant Effect Predictor（VEP）用于注释与 AD 相关的变体。对注释的错义变体进行了 PolyPhen-2、SNP&Go、PredictSNP 服务器的分析，这些服务器用于根据蛋白质序列信息预测选定错义变体的致病性。DynaMut 和 DUET 服务器用于通过整合蛋白质结构信息来确定由于氨基酸变化导致的蛋白质稳定性。与 AD 相关的错义变化被注释到 26 种蛋白质，并在我们的研究中进一步分析。在经过严格的数据过滤步骤后，确定了 15 个候选变体（13 种蛋白质），并对其进行了序列和结构分析。最后，在这项计算机研究中，在 ACKR2（V41A）、APOE（R176C）、ATP8B4（G395S）、LAMB2（E987K）和 TOMM40（R239W）中鉴定出五个有害的非 synonymous单核苷酸多态性（nsSNP），这些发现随后得到了现有体内和体外文献的支持。本研究不仅为 AD 复杂的发病机制提供了宝贵的见解，而且提供了独特的视角，为未来更全面的研究铺平了道路，这些研究旨在揭示导致 AD 发展和进展的分子复杂性。然而，至关重要的是，需要进行进一步的严格体内和体外实验，以验证和扩展这里提出的发现。
