Anjum Farah, Bakhuraysah Maha M, Hulbah Maram Jameel, Alsharif Abdulaziz, Mohammad Taj, Hassan Md Imtaiyaz
Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, Taif, 21944, Saudi Arabia.
King Salman Center for Disability Research, Riyadh, 11614, Saudi Arabia.
J Mol Neurosci. 2025 Aug 7;75(3):99. doi: 10.1007/s12031-025-02388-7.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron degeneration and a median survival of 3-5 years post-diagnosis. While the etiology of ALS remains elusive, mutations in SOD1, encoding the Cu/Zn superoxide dismutase enzyme, are strongly associated with familial ALS (fALS). These mutations promote a toxic gain-of-function, primarily through SOD1 misfolding and aggregation. We systematically assessed 244 SOD1 missense mutations using a multi-tiered computational framework encompassing structural, functional, and pathogenic predictors. Sequence-based predictors (SIFT, PolyPhen-2, FATHMM) and structure-guided tools (mCSM, PremPS, DynaMut2) identified 79 destabilizing mutations, 64 of which were classified as pathogenic by phenotype predictors (PhD-SNP, SNPs&GO, MutPred2). Twelve mutations resided in evolutionarily conserved regions, with eight (D84N, G73C, H72Y, P67A, P67R, P67S, R144G, S60I) exhibiting pronounced aggregation propensity via SODA analysis. Notably, H72Y disrupts a zinc-binding residue critical for structural integrity and catalysis. Protein-protein interaction networks linked SOD1 to ALS-associated pathways, highlighting its involvement in oxidative stress and protein homeostasis. Our integrative approach highlights the power of computational genomics in unraveling mutation-driven SOD1 dysfunction, offering mechanistic insights into ALS pathogenesis and guiding therapeutic strategies focused on aggregation-prone variants.
肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征为运动神经元进行性退化，诊断后的中位生存期为3至5年。虽然ALS的病因仍不明确，但编码铜/锌超氧化物歧化酶的SOD1基因突变与家族性ALS（fALS）密切相关。这些突变主要通过SOD1错误折叠和聚集促进毒性功能获得。我们使用包含结构、功能和致病性预测因子的多层计算框架，系统评估了244个SOD1错义突变。基于序列的预测因子（SIFT、PolyPhen-2、FATHMM）和结构导向工具（mCSM、PremPS、DynaMut2）识别出79个不稳定突变，其中64个被表型预测因子（PhD-SNP、SNPs&GO、MutPred2）归类为致病性突变。12个突变位于进化保守区域，通过SODA分析，其中8个（D84N、G73C、H72Y、P67A、P67R、P67S、R144G、S60I）表现出明显的聚集倾向。值得注意的是，H72Y破坏了对结构完整性和催化至关重要的锌结合残基。蛋白质-蛋白质相互作用网络将SOD1与ALS相关途径联系起来，突出了其在氧化应激和蛋白质稳态中的作用。我们的综合方法突出了计算基因组学在揭示突变驱动的SOD1功能障碍方面的作用，为ALS发病机制提供了机制性见解，并指导针对易聚集变体的治疗策略。
