Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA; Medical Scientist Training Program, Penn State College of Medicine, Hershey, PA, USA.
Department of Pharmacology, Penn State College of Medicine, Hershey, PA, USA; Department of Biomedical Engineering, Penn State University, University Park, PA, USA.
Structure. 2024 Oct 3;32(10):1776-1792.e5. doi: 10.1016/j.str.2024.08.002. Epub 2024 Aug 28.
Misfolded species of superoxide dismutase 1 (SOD1) are associated with increased death in amyotrophic lateral sclerosis (ALS) models compared to insoluble protein aggregates. The mechanism by which structurally independent SOD1 trimers cause cellular toxicity is unknown but may drive disease pathology. Here, we uncovered the SOD1 trimer interactome-a map of potential tissue-selective protein-binding partners in the brain, spinal cord, and skeletal muscle. We identified binding partners and key pathways associated with SOD1 trimers and found that trimers may affect normal cellular functions such as dendritic spine morphogenesis and synaptic function in the central nervous system and cellular metabolism in skeletal muscle. We discovered SOD1 trimer-selective enrichment of genes. We performed detailed computational and biochemical characterization of SOD1 trimer protein binding for septin-7. Our investigation highlights key proteins and pathways within distinct tissues, revealing a plausible intersection of genetic and pathophysiological mechanisms in ALS through interactions involving SOD1 trimers.
与不溶性蛋白聚集体相比，错误折叠的超氧化物歧化酶 1（SOD1）物种与肌萎缩侧索硬化症（ALS）模型中的死亡率增加有关。结构上独立的 SOD1 三聚体引起细胞毒性的机制尚不清楚，但可能驱动疾病病理。在这里，我们揭示了 SOD1 三聚体的互作组——大脑、脊髓和骨骼肌中潜在的组织选择性蛋白结合伴侣图谱。我们确定了与 SOD1 三聚体相关的结合伴侣和关键途径，发现三聚体可能会影响正常的细胞功能，如中枢神经系统中的树突棘形态发生和突触功能，以及骨骼肌中的细胞代谢。我们发现了 SOD1 三聚体选择性富集的基因。我们对 septin-7 的 SOD1 三聚体蛋白结合进行了详细的计算和生化表征。我们的研究突出了不同组织中的关键蛋白和途径，通过涉及 SOD1 三聚体的相互作用，揭示了 ALS 中遗传和病理生理机制的明显交集。
