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

Proceedings of the National Academy of Sciences - PNAS, 2012-03, Vol.109 (13), p.5074-5079 [Peer Reviewed Journal]

copyright © 1993-2008 National Academy of Sciences of the United States of America ;Copyright National Academy of Sciences Mar 27, 2012 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1115402109 ;PMID: 22416121

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Title:
over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1
Author: Guareschi, Stefania ; Cova, Emanuela ; Cereda, Cristina ; Ceroni, Mauro ; Donetti, Elena ; Bosco, Daryl A ; Trotti, Davide ; Pasinelli, Piera
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
Is Part Of: Proceedings of the National Academy of Sciences - PNAS, 2012-03, Vol.109 (13), p.5074-5079
Description: 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.
Publisher: United States: National Academy of Sciences
Language: English
Identifier: ISSN: 0027-8424
EISSN: 1091-6490
DOI: 10.1073/pnas.1115402109
PMID: 22416121
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
PubMed Central

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

copyright © 1993-2008 National Academy of Sciences of the United States of America ;Copyright National Academy of Sciences Mar 27, 2012 ;ISSN: 0027-8424 ;EISSN: 1091-6490 ;DOI: 10.1073/pnas.1115402109 ;PMID: 22416121

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