Table 8_A systematic review and functional in-silico analysis of genes and variants associated with amyotrophic lateral sclerosis.xlsx

IntroductionAmyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease characterized by the deterioration of upper and lower motor neurons. Affected patients experience progressive muscle weakness, including difficulty in swallowing and breathing; being respiratory failure the main cause of death. However, there is considerable phenotypic heterogeneity, and its diagnosis is based on clinical criteria. Moreover, most ALS cases remain unexplained, suggesting a complex genetic background.
MethodsTo better understand the molecular mechanisms underlying ALS, we comprehensively analyzed, filtered and classified genes from 4,293 abstracts retrieved from PubMed, 7,343 variants from ClinVar, and 33 study accessions from GWAS catalog. To address the importance of ALS-associated genes and variants, we performed diverse bioinformatic analyses, including gene set enrichment, drug-gene interactions, and differential gene expression analysis using public databases.
ResultsOur analysis yielded a catalog of 300 genes with 479 ALS-associated variants. Most of these genes and variants are found in coding regions and their proteins are allocated to the cytoplasm and the nucleus, underscoring the relevance of toxic protein aggregates. Moreover, protein-coding genes enriched ALS-specific pathways, for example spasticity, dysarthria and dyspnea. ALS-associated genes are targeted by commonly used drugs, including Riluzole and Edaravone, and by the recently approved antisense oligonucleotide therapy (Tofersen). Moreover, we observed transcriptional dysregulation of ALS-associated genes in peripheral blood mononuclear cell and postmortem cortex samples.
ConclusionOverall, this ALS catalog can serve as a foundational tool for advancing early diagnosis, identifying biomarkers, and developing personalized therapeutic strategies.

引言
肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种致命的进行性神经退行性疾病，以上下运动神经元退行性病变为特征。受累患者会出现进行性肌肉无力，包括吞咽与呼吸困难；呼吸衰竭为其主要死亡原因。然而该病存在显著的表型异质性，诊断需依据临床标准。此外，多数ALS病例病因未明，提示其遗传背景复杂。
方法
为更深入解析ALS的分子致病机制，本研究对从PubMed（PubMed）检索得到的4293篇文献摘要、ClinVar（ClinVar）数据库中的7343个变异以及全基因组关联分析目录（GWAS Catalog）中的33项研究条目开展了全面的基因分析、筛选与分类。为明确ALS相关基因与变异的重要性，我们进行了多维度生物信息学分析，包括基因集富集分析、药物-基因相互作用分析，以及利用公共数据库开展的差异基因表达分析。
结果
本研究最终构建了包含300个基因与479个ALS相关变异的数据集。其中绝大多数基因与变异位于蛋白编码区，其编码蛋白主要定位于细胞质与细胞核，这凸显了毒性蛋白聚集的相关性。此外，编码蛋白基因显著富集于ALS特异性通路，例如痉挛、构音障碍与呼吸困难相关通路。ALS相关基因可被临床常用药物（如利鲁唑、依达拉奉）以及近期获批的反义寡核苷酸疗法（Tofersen）靶向。此外，我们在外周血单个核细胞与死后皮层样本中均观察到ALS相关基因的转录失调现象。
结论
总体而言，本ALS数据集可作为推进ALS早期诊断、识别疾病生物标志物以及开发个性化治疗策略的基础性研究工具。