TY - JOUR
T1 - Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS
AU - Brotherton, Terrell E.
AU - Li, Yingjie
AU - Cooper, Deborah
AU - Gearing, Marla
AU - Julien, Jean Pierre
AU - Rothstein, Jeffrey D.
AU - Boylan, Kevin
AU - Glass, Jonathan D.
PY - 2012/4/3
Y1 - 2012/4/3
N2 - 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 pathologically affected tissue in mutant SOD1 ALS rodent models and humans, specifically motor neuron populations, suggests that this antibody may recognize a "toxic" form of the mutant SOD1 protein.
AB - 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 pathologically affected tissue in mutant SOD1 ALS rodent models and humans, specifically motor neuron populations, suggests that this antibody may recognize a "toxic" form of the mutant SOD1 protein.
KW - Aggregate
KW - Misfold
KW - Soluble
UR - http://www.scopus.com/inward/record.url?scp=84859452121&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859452121&partnerID=8YFLogxK
U2 - 10.1073/pnas.1115009109
DO - 10.1073/pnas.1115009109
M3 - Article
C2 - 22431618
AN - SCOPUS:84859452121
SN - 0027-8424
VL - 109
SP - 5505
EP - 5510
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 14
ER -