Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's Disease, is a devastating motor neuron degenerative disease whose etiology and pathogenesis remain poorly understood. Most cases of ALS (~90%) are sporadic (SALS) and occur in the absence of genetic associations. About 20% of the 10% familial ALS (FALS) cases are due to mutations in the copper, zinc superoxide dismutase (SOD1) gene. Molecular evidence for a common pathogenesis of SALS and FALS has remained elusive. Here an undiscovered feature of SOD1 common to both SOD1-linked FALS and SALS, but not present in normal or non-ALS disease cases, is revealed in electrophoretic gels. Biotinylation reveals an ALS-specific SOD1-containing protein species immunoreactive to a peptide-specific rabbit antiserum to human SOD1. Trypsin digestion of the spot excised from the gels, followed by nanospray mass spectrometry analysis reveals a suite of peptides from SOD1. The results suggest a shared molecular event involving a known target gene as a common step in etiology and pathogenesis between SALS and FALS, and may have important implications for ALS diagnosis and therapeutics.