Dokholyan Nikolay, Hnath Brianna, Dokholyan Rachel, Simmons Zachary
Penn State College of Medicine.
Penn State Health.
Res Sq. 2025 Jul 15:rs.3.rs-6941118. doi: 10.21203/rs.3.rs-6941118/v1.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that leads to the loss of motor neurons, resulting in paralysis and death. Currently, there are no specific biomarkers available for diagnosing ALS. As a result, diagnosis currently relies on excluding other conditions, which forces patients to endure months or even years of uncertainty. The absence of a specific, reliable diagnostic tool has hindered both early intervention and therapeutic progress. Here we develop a novel synthetic antibody that can detect a toxic form of a known protein linked to ALS. This trimeric assembly of superoxide dismutase 1 (SOD1) is a soluble, structurally distinct oligomer that is highly toxic in cell models. The antibody selectively binds this trimer and differentiates individuals with the disease from healthy people and from those with other neurodegenerative diseases (Alzheimer's and Parkinson's disease). This breakthrough provides the first disease-specific diagnostic tool for this condition and reveals a shared pathological signature across patients, even in cases without genetic mutations. After decades without a specific diagnostic tool, this antibody signifies a long-awaited breakthrough, finally offering clinicians and researchers a reliable window into ALS pathology.
肌萎缩侧索硬化症(ALS)是一种致命的神经退行性疾病,会导致运动神经元丧失,最终导致瘫痪和死亡。目前,尚无用于诊断ALS的特异性生物标志物。因此,目前的诊断依赖于排除其他病症,这使得患者不得不忍受数月甚至数年的不确定性。缺乏一种特异性、可靠的诊断工具阻碍了早期干预和治疗进展。在此,我们开发了一种新型合成抗体,它能够检测与ALS相关的一种已知蛋白质的毒性形式。这种超氧化物歧化酶1(SOD1)的三聚体组装体是一种可溶性、结构独特的寡聚体,在细胞模型中具有高度毒性。该抗体选择性地结合这种三聚体,并将患有该疾病的个体与健康人以及患有其他神经退行性疾病(阿尔茨海默病和帕金森病)的人区分开来。这一突破为该病症提供了首个疾病特异性诊断工具,并揭示了患者之间共有的病理特征,即使在没有基因突变的情况下也是如此。在数十年没有特异性诊断工具之后,这种抗体标志着一个期待已久的突破,终于为临床医生和研究人员提供了一个了解ALS病理学的可靠窗口。