We recently reported that degenerating motor neurons of superoxide dismutase mutant 1 (SOD1) rodents exhibit immunoreactivity to P2X(4) antibodies. Neurons with strong P2X(4)-like immunoreactivity (P2X(4)-LIR) do not show an apoptotic phenotype and are often associated with microglial cells that display neuronophagic activity. Western blot analysis showed that P2X(4) antibodies recognize not only the P2X(4) adenosine triphosphate receptor protein but also a hitherto unidentified low-molecular weight band. Here, we identify the molecular counterpart of the strong P2X(4)-LIR observed in association with neuronal degeneration in SOD1 animals. After matrix-assisted laser desorption/ionization time-of-flight, we found that the low-molecular weight P2X(4)-immunoreactive protein was SOD1. Further analysis demonstrated that the P2X(4) antibody recognizes a form of misfolded mutant SOD1 that is expressed in neuronal cells undergoing degeneration but not in glial cells. Cross-reactivity could have been caused by the abnormal exposure of an epitope in the inner hydrophobic region of SOD1 that shared structural homology with the P2X(4)-immunizing peptide used for raising the antibody. No positive P2X(4) immunostaining was detected in mice overexpressing human wild-type SOD1. Intracerebral injections of affinity chromatography-isolated P2X(4)-immunoreactive SOD1 species promote microglial and astroglial activation. We conclude that neuronal SOD1 conformers with P2X(4)-LIR may have pathogenetic relevance in the promotion of neuroinflammation.