A molecular mechanism regulating pathological aggregation of SOD1 proteins

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ALS-causing mutations facilitate aggregation of SOD1, upon which significant structural changes of SOD1 have been assumed; however, a structure of protein aggregate remains obscure. Here, by utilizing mass spectrometry, I have identified a protease-resistant core in wild-type as well as ALS-causing mutant SOD1 aggregates. SOD1 aggregates exhibit mutation-dependent structural polymorphism, which further regulates biochemical properties of aggregates such as solubility. Based upon these results, I propose a new pathomechanism of fALS in which mutation-dependent structural polymorphism of SOD1 aggregates can affect disease phenotypes.