A novel oxidative pathway for human SOD1 aggregation is revealed and may contribute to ALS pathology

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by Ohara Augusto

ALS (amyotrophic lateral sclerosis) is a fatal disease characterized by the degeneration of motor neurons, resulting in progressive muscle weakness, atrophy, paralysis and death. Most cases of ALS are sporadic but about 10% of the cases have a genetic basis.ALS-causing mutations have been identified in several genes, but the mutation of Cu,Zn superoxide dismutase gene (SOD1) is the most studied and responsible for about 20% of the familial cases. SOD1-linked ALS patients exhibit pathology and symptoms similar to those of sporadic ALS patients, leading to the hypothesis that both forms of the disease have a common pathogenic mechanism. This hypothesis led to many advances in the understanding of the disease but its pathogenic mechanism remains unclear. Our group has been exploring a role for oxidative modifications of hSOD1 in ALS pathology, based on several lines of evidence. Among them, the remarkable stability of hSOD1WT and several of its ALS-associated suggests that hSOD1 oxidation precedes its conversion to the unfolded and aggregated forms consistently found in ALS patients. Also, hSOD1 possesses a bicarbonate-dependent peroxidase activity, which oxidizes its own solvent-exposed Trp32 residue. The resulting products are specific for simian SOD1s, which contain the Trp32 residue. The aims of this work were to examine whether the bicarbonate-dependent peroxidase activity of hSOD1 (hSOD1WT and hSOD1G93A mutant) triggers aggregation of the enzyme and to comprehend the role of the Trp32 residue in the process. The results showed that the Trp32 residues of both enzymes are oxidized to a similar extent to hSOD1-derived tryptophanyl radicals. These radicals decayed to hSOD1-N-formylkynurenine and hSOD1-kynurenine or to a hSOD1 covalent dimer cross-linked by a ditryptophan bond, causing hSOD1 unfolding, oligomerization and non-amyloid aggregation. The latter process was inhibited by tempol, which recombines with the hSOD1-derived tryptophanyl radical, and did not occur in the absence of bicarbonate or with enzymes that lack the Trp32 residue (bovine SOD1 and hSOD1W32F mutant). The results support a role for the oxidation products of the hSOD1-Trp32 residue, particularly the covalent dimer cross-liked by the ditryptophan bond, in triggering the non-amyloid aggregation of hSOD1. Therefore, the ditryptophan cross-link may become a useful target for therapeutic intervention but, to this end, further studies will be required. Nonetheless, these studies provided a novel route for the non-amyloid aggregation of hSOD1, a pathway that relies on an oxidative modification caused by its own bicarbonate-dependent peroxidase activity.

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F. R. Coelho, A. Iqbal, E. Linares, D. F. Silva, F. S. Lima, I. M. Cuccovia, O. Augusto.
Oxidation of the tryptophan 32 residue of human superoxide dismutase 1 caused by its bicarbonate-dependent peroxidase activity triggers the non-amyloid aggregation of the enzyme.
The Journal of Biological Chemistry, 289: 30690-701, 2014. | http://dx.doi.org/10.1074/jbc.M114.586370

Ohara Augusto, PhD.
Professor at Department of Biochemistry,
Institute of Chemistry, University of São Paulo, Brazil
Director of RIDC (CEPID) Redoxoma

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