Koehn Liam M, Steele Joel R, Schittenhelm Ralf B, Nicolazzo Joseph A
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
Monash Proteomics and Metabolomics Platform, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3168, Australia.
J Proteome Res. 2025 Apr 4;24(4):1956-1970. doi: 10.1021/acs.jproteome.4c00990. Epub 2025 Mar 21.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder that has no cure. The underlying mechanistic details of sex differences in the ALS spinal cord, the site of disease onset, are not understood to an extent that could guide novel drug development. To address this, the spinal cords of 120-day-old wild-type (WT) and SOD1 (familial mouse model of ALS with mutant superoxide dismutase 1) mice were subjected to untargeted, quantitative proteomics using tandem mass tag acquisition on high-resolution mass spectrometric instrumentation. Compared to WT, both male and female SOD1 spinal cords exhibited an upregulation of neuroinflammatory cascades of both peripheral and central origins, as well as a downregulation of proteins reflective of death and dysfunction of cells within the spinal cord. However, female and male SOD1 mouse spinal cords exhibited sex-specific differences in proteins compared to respective WT that related to immune response, as well as cellular structure, function, and homeostasis. The proteomic datasets presented provide entire cohort and sex-specific spinal cord drug targets and disease biomarkers in the SOD1 mouse model of ALS that may guide future drug development and sex selection in preclinical study designs utilizing the SOD1 model.
肌萎缩侧索硬化症（ALS）是一种无法治愈的进行性神经退行性疾病。ALS发病部位是脊髓，关于脊髓中性别差异的潜在机制细节，目前尚未了解到足以指导新型药物研发的程度。为了解决这一问题，我们使用高分辨率质谱仪上的串联质量标签采集技术，对120日龄野生型（WT）小鼠和SOD1（突变型超氧化物歧化酶1的家族性ALS小鼠模型）小鼠的脊髓进行了非靶向定量蛋白质组学分析。与WT相比，雄性和雌性SOD1小鼠的脊髓均表现出外周和中枢来源的神经炎症级联反应上调，以及反映脊髓内细胞死亡和功能障碍的蛋白质下调。然而，与各自的WT相比，雌性和雄性SOD1小鼠脊髓在与免疫反应以及细胞结构、功能和稳态相关的蛋白质方面表现出性别特异性差异。本文提供的蛋白质组学数据集为ALS的SOD1小鼠模型提供了整个队列以及性别特异性的脊髓药物靶点和疾病生物标志物，这可能会指导未来利用SOD1模型进行的临床前研究设计中的药物开发和性别选择。
