Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS

作者：Terrell Brotherton, Yingjie Li, Deborah Cooper, Marla Gearing, Jean‐Pierre Julien, Jeffrey D. Rothstein, Khrista Boylan, Jonathan D. Glass · 发表于：Proceedings of the National Academy of Sciences · 年份：2012 · DOI：10.1073/pnas.1115009109 · 被引用次数：123 · 研究领域：Amyotrophic Lateral Sclerosis Research、Prion Diseases and Protein Misfolding、Biochemical Acid Research Studies

Mutations in the gene encoding superoxide dismutase 1 (SOD1) account for about 20% of the cases of familial amyotrophic lateral sclerosis (fALS). It is not known how the mutant protein causes disease, or why only a subset of cell types (motor neurons) are targeted. The aggregation and misfolding of mutant SOD1 are implicated in disease pathogenesis in both animal models and humans. We used a monoclonal antibody, C4F6, which specifically reacts with mutant and/or "misfolded" SOD1, to investigate the regional distribution of mutant SOD1 protein in rodent and human tissues. C4F6 reacted only with mutant SOD1 and showed remarkable selectivity for disease-affected tissues and cells. Tissue not affected by disease but containing high levels of mutant protein (sensory neurons) did not stain with C4F6. Additionally, C4F6 intensely stained some motor neurons while leaving adjacent motor neurons unstained. Although C4F6 was generated against the G93A SOD1 mutant, it also recognized other SOD1 mutants. In human autopsy tissues from patients carrying SOD1 mutations, C4F6 identified skein-like intracellular inclusions in motor neurons, similar to those seen in rodents, and again stained only a subset of motor neurons. In spinal cords from patients with sporadic ALS, other neurodegenerative diseases, and normal controls, C4F6-immunoreactive inclusions were not detected, but the antibody did reveal diffuse immunostaining of some spinal motor neurons. The ability of C4F6 to differentiate pat...