Journal Article

Fast and slow strains of misfolded mutant superoxide dismutase 1 in familial amyotrophic lateral sclerosis

Fromholt, Susan, Glass, Jonathan D., Borchelt, David R., Ayers, Jacob I., Xu, Guilian, Lopez, Amanda, Chakrabarty, Paramita, Dillon, Kristy, Brkic, Selma, Ostrow, Lyle W.

2026

Overview

Mutations in superoxide dismutase 1 (SOD1) account for ~ 10% of familial amyotrophic lateral sclerosis (fALS) cases. Most SOD1 ALS cases show a 2–5 year clinical course, but a subset of patients exhibit a slowly progressing illness lasting 10–20 years. Substantial evidence indicates that disease-causing mutations in SOD1 promote misfolding and aggregation. Spinal tissue homogenates from paralyzed transgenic mice containing misfolded mutant SOD1 accelerate paralysis when injected into the spine or sciatic nerve of young mutant SOD1 transgenic mice. Using this prion-like seeding model in G85R-SOD1:YFP transgenic mice to initiate the disease process, we show that human SOD1 variants associated with rapidly progressing ALS produce SOD1-ALS strains that cause paralysis earlier than mutations associated with slowly progressing disease. Our findings suggest that the heterogeneous clinical presentations of different SOD1 mutations in ALS could be linked to prion-like strain attributes that govern the templating and propagation kinetics of misfolded SOD1.

• Publisher: BioMed Central,Nature Publishing Group,BMC
• Subject: Amyotrophic lateral sclerosis / Asymptomatic / Biomedical and Life Sciences / Biomedicine / Mutation / Neurology / Neurosciences / Paralysis / Pathology / Prion / Propagation / Protease inhibitors / Proteins / Spinal cord / Strains / Superoxide dismutase-1 / Tissues / Transgenic animals