SOD1 trimers in amytrophic lateral sclerosis
Open Access
- Author:
- Choi, Esther
- Graduate Program:
- Biomedical Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 25, 2024
- Committee Members:
- Xuemei Huang, Major Field Member
Zachary Simmons, Major Field Member
Elizabeth Proctor, Outside Unit Member
James Broach, Outside Field Member
Nikolay Dokholyan, Chair & Dissertation Advisor
Lisa Shantz, Program Head/Chair - Keywords:
- Amyotrophic lateral sclerosis
neurodegeneration
SOD1 - Abstract:
- Misfolded soluble trimeric species of superoxide dismutase 1 (SOD1) have been linked to increased cell death in neuron-like cell models and greater disease severity in amyotrophic lateral sclerosis (ALS) patients when compared to insoluble protein aggregates. However, the role of structurally independent SOD1 trimers in cellular toxicity remains unknown, potentially serving as a driver of disease pathology. To establish a foundation for comprehending the involvement of SOD1 trimers in ALS, we investigated the SOD1 trimer interactome—a map delineating potential tissue-selective protein binding partners in the brain, spinal cord, and skeletal muscle. Through this exploration, we identified binding partners and key pathways associated with SOD1 trimers, drawing comparisons with those of wild-type SOD1 dimers. Additionally, we utilized transcriptomic data from motor neuron-like cells (NSC-34s) expressing SOD1 trimers to pinpoint essential pathways. A detailed computational and biochemical characterization was performed for septin-7, a SOD1 trimer binding partner. In our discussions, we explore the evolving role of induced pluripotent stem cells (iPSCs) as a disease model and consider the future implications of oligomers in ALS research. Our studies unveil a dual impact of SOD1 trimer toxicity, affecting both nerves and muscles and suggest plausible pathways in the etiology of ALS.