Revealing the role of post-translational modifications in superoxide dismutase fibril formation – seeking the molecular connection between familial- and sporadic ALS

The research goal is to unravel the molecular effects of posttranslational modifications (PTMs) of superoxide dismutase 1 (SOD1) in amyloid formation.

Misfolding of SOD1 is associated with the most common form of familial amyotrophic lateral sclerosis (ALS), where mutations lead to SOD1 aggregation and gain of toxicity.

Wild-type SOD1 aggregates have also been associated with sporadic ALS, implying a general role of SOD1 in ALS pathogenesis. Recent research has revealed that different types of cellular stress affect the PTMs of SOD1.

Similar to mutations, PTMs change the chemical properties of SOD1, suggesting a possible molecular mechanism behind the triggering of aggregation and gain-of-toxicity of wild-type SOD1 that leads to sporadic ALS. In the present project I will combine my expertise built during two postdoc periods.

State-of-the-art methods to produce SOD1 variants with natural PTMs through incorporation of non-canonical amino acids in E. coli will be combined with an integrative biophysical approach to study the effects of PTMs on fibril formation.

My preliminary results show the power of combining NMR, SAXS, mass-spectrometry and cryo-EM to obtain a complete and time-resolved description of the entire fibril formation pathway. A combined analysis will reveal how different PTMs interfere with and change the mechanism of SOD1 fibrillation. The ultimate goal is to provide a molecular basis for rational design of molecules targeting toxic oligomers of SOD1.