title: An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1.
abstract: 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.
authors.affiliation: Weinberg Unit for ALS Research, Department of Neuroscience, Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, PA 19107, USA.
authors.forename: Stefania
authors.initials: S
authors.lastname: Guareschi
authors.forename: Emanuela
authors.initials: E
authors.lastname: Cova
authors.forename: Cristina
authors.initials: C
authors.lastname: Cereda
authors.forename: Mauro
authors.initials: M
authors.lastname: Ceroni
authors.forename: Elena
authors.initials: E
authors.lastname: Donetti
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Bosco
authors.forename: Davide
authors.initials: D
authors.lastname: Trotti
authors.forename: Piera
authors.initials: P
authors.lastname: Pasinelli
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000473:pathology; D001933:Brain Stem / Q000473:pathology*; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D010084:Oxidation-Reduction / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D020836:Protein Structure, Quaternary; D021381:Protein Transport / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013482:Superoxide Dismutase / Q000009:adverse effects* / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity
chemical_list: D050505:Mutant Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013482:Superoxide Dismutase