Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis

Significance The identification of aberrant SOD1 WT species accumulating in the spinal cord during aging could reveal pathogenic species involved in sporadic (s)ALS. Using a combination of biochemical approaches, we discovered that disulfide–cross-linked SOD1 WT aggregates rise before other abnormal protein species during aging and are significantly increased in sALS spinal cord tissue. We also found that endoplasmic reticulum stress stimulates accumulation of these species, with involvement of tryptophan-32 oxidation. These results establish a connection between SOD1 WT aggregation and a major proteostasis network affected in ALS.