over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1

• Published in: Proceedings of the National Academy of Sciences - PNAS 2012-03, Vol.109 (13), p.5074-5079
• Main Authors: Guareschi, Stefania, Cova, Emanuela, Cereda, Cristina, Ceroni, Mauro, Donetti, Elena, Bosco, Daryl A, Trotti, Davide, Pasinelli, Piera
• Format: Article
• Language: English
• Subjects: Aggregation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - enzymology; Amyotrophic Lateral Sclerosis - pathology; Antibodies; astrocytes; Biological Sciences; Biomarkers; Brain Stem - pathology; carbonyl compounds; Cell aggregates; Cells; copper; derivatization; Female; Genetic mutation; Humans; Lymphocytes - drug effects; Lymphocytes - enzymology; Male; Middle Aged; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; Motor neurons; Mutant Proteins - chemistry; Mutant Proteins - metabolism; Mutant Proteins - toxicity; mutants; Mutation; Neurons; Oxidation; Oxidation-Reduction - drug effects; Oxidative stress; patients; post-translational modification; Protein Binding - drug effects; Protein Structure, Quaternary; Protein Transport - drug effects; Proto-Oncogene Proteins c-bcl-2 - metabolism; sclerosis; superoxide dismutase; Superoxide Dismutase - adverse effects; Superoxide Dismutase - chemistry; Superoxide Dismutase - metabolism; Superoxide Dismutase - toxicity; Superoxides; Toxicity; zinc
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1115402109

Recent studies suggest that Cu/Zn superoxide dismutase (SOD1) could be pathogenic in both familial and sporadic amyotrophic lateral sclerosis (ALS) through either inheritable or nonheritable modifications. The presence of a misfolded WT SOD1 in patients with sporadic ALS, along with the recently reported evidence that reducing SOD1 levels in astrocytes derived from sporadic patients inhibits astrocyte-mediated toxicity on motor neurons, suggest that WT SOD1 may acquire toxic properties similar to familial ALS-linked mutant SOD1, perhaps through posttranslational modifications. Using patients’ lymphoblasts, we show here that indeed WT SOD1 is modified posttranslationally in sporadic ALS and is iper-oxidized (i.e., above baseline oxidation levels) in a subset of patients with bulbar onset. Derivatization analysis of oxidized carbonyl compounds performed on immunoprecipitated SOD1 identified an iper-oxidized SOD1 that recapitulates mutant SOD1-like properties and damages mitochondria by forming a toxic complex with mitochondrial Bcl-2. This study conclusively demonstrates the existence of an iper-oxidized SOD1 with toxic properties in patient-derived cells and identifies a common SOD1-dependent toxicity between mutant SOD1-linked familial ALS and a subset of sporadic ALS, providing an opportunity to develop biomarkers to subclassify ALS and devise SOD1-based therapies that go beyond the small group of patients with mutant SOD1.