Aberrant self-assembly and toxicity of wild-type and mutant superoxide dismutase 1 (SOD1) has been widely examined in silico, in vitro, and in transgenic animal models of amyotrophic lateral sclerosis (ALS). Detailed examination of the protein in disease-affected tissues from ALS patients, however, remains scarce.
We employed histological, biochemical and analytical techniques to profile alterations to SOD1 protein deposition, subcellular localization, maturation and post-translational modification in post-mortem spinal cord tissues from ALS cases and controls. Tissues were dissected into ventral and dorsal spinal cord grey matter to assess the specificity of alterations within regions of motor neuron degeneration.
We provide evidence of the mislocalization and accumulation of structurally-disordered, immature SOD1 protein conformers in spinal cord motor neurons of SOD1-linked and non-SOD1-linked familial ALS cases, and sporadic ALS cases, compared with control motor neurons. These changes were collectively associated with instability and mismetallation of enzymatically-active SOD1 dimers, as well as alterations to SOD1 post-translational modifications and molecular chaperones governing SOD1 maturation. Atypical changes to SOD1 protein were largely restricted to regions of neurodegeneration in ALS cases, and clearly differentiated all forms of ALS from controls. Substantial heterogeneity in the presence of these changes was also observed between ALS cases.
Our data demonstrates that varying forms of SOD1 proteinopathy are a common feature of all forms of ALS, and support the presence of one or more convergent biochemical pathways leading to SOD1 proteinopathy in ALS. The majority of these alterations are specific to regions of neurodegeneration, and may therefore constitute valid targets for therapeutic development.