Misfolding and aggregation of Cu/Zn superoxide dismutase (SOD1) enzyme is associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). The remarkable stability of SOD1 suggests exogenous factors contributing to the dramatic destabilization of this enzyme. We have previously determined that SOD1 from human tissue is extensively post-translationally modified, with the most prevalent modifications being glutathionylation at Cys-111 and phosphorylation at Thr-2. We found that glutathionylation significantly destabilizes SOD1WT dimers, increasing the equilibrium dissociation constant approximately 1,000-fold, such that its stability is comparable to the A4V FALS-causative mutation. SOD1A4V is destabilized by glutathionylation even further. We show that glutathionylation has distinct effects on different ALS-linked SOD1 mutants, which correspond to changes in the composition of the dimer interface. We demonstrate the formation of soluble oligomers at the early stages of SOD1 aggregation. These oligomers feature an epitope-specific to disease-relevant misfolded SOD1, which is recognized by the C4F6 antibody (a marker of toxic species). Using a battery of computational and experimental approaches we demonstrate that specific trimeric oligomers are responsible for neuronal death. We also demonstrate that large insoluble aggregates are protective of neurons. These findings challenge the amyloid cascade hypothesis and propose a new view of the etiologies of aggregation-related diseases.

From etiology to therapeutics of Lou Gehrig’s disease

ACS Spring Meeting 2021

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