Project 171148

Mutations in the superoxide dismutase (SOD1) gene are responsible for ~20% familial ALS. This corresponds to only ~2% ALS cases. For the vast majority of ALS cases which are sporadic, the causes remain unknown. Recently, our group reported that oxidized wild-type (WT) SOD1 can acquire properties of ALS-linked mutant SOD1 species. Moreover, we have generated a panel of monoclonal antibodies that recognize misfolded SOD1 species produced by SOD1 mutations and that bind epitopes buried in the intact WT SOD1 unless the protein is unfolded. Preliminary data show that some of these specific antibodies can detect SOD1 in post-mortem spinal cord samples from sporadic ALS patients. This proposal is based on the hypothesis that sporadic ALS cases may share with familial ALS a common pathogenic pathway involving misfolding of SOD1. In the next three years, we propose to use our specific antibodies to investigate the misfolded SOD1 species associated with sporadic ALS.

using monoclonal antibodies to detect misfolded SOD1 in sporadic ALS, suggesting a common pathogenic pathway with familial ALS