2024-10-11 ペンシルベニア州立大学(PennState)
<関連情報>
- https://www.psu.edu/news/research/story/toxic-protein-may-contribute-als-development
- https://www.cell.com/structure/fulltext/S0969-2126(24)00319-8
両刃の剣を解き明かす:SOD1三量体は組織選択的毒性を持ち、運動ニューロン様細胞でセプチン-7と結合する Unveiling the double-edged sword: SOD1 trimers possess tissue-selective toxicity and bind septin-7 in motor neuron-like cells
Esther Sue Choi∙ Brianna Hnath∙ Congzhou Mike Sha∙ Nikolay V. Dokholyan
Structure Published:August 28, 2024
DOI:https://doi.org/10.1016/j.str.2024.08.002
Graphical abstract
Highlights
•SOD1 trimers but not dimers bind neuronal regulator protein, septin-7
•SOD1 trimers may be at the intersection of pathophysiological mechanisms in ALS
Summary
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.
