Early Steps in Oxidation-Induced SOD1 Misfolding: Implications for Non-Amyloid Protein Aggregation in Familial ALS

Mulligan, Vikram Khipple; Kerman, Aaron; Laister, Rob C.; Sharda, Priya; Arslan, Pharhad Eli; Chakrabartty, Avijit

doi:10.1016/j.jmb.2012.04.016

Cited by 47 publications

(69 citation statements)

References 84 publications

(156 reference statements)

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“…7). Our hypothesis, thus, also encompasses aspects of the oxidative damage hypothesis, which purports that reactive oxygen species within highly metabolic neurons put SOD at risk for oxidative damage; it was observed for hydrogen peroxidemediated oxidative damage to active site histidine ligands, leading to copper ion release (102). Furthermore, slightly destabilized mutant proteins may be more sensitive to the effects of oxidative modification, such as glutathionylation (103), leading to their dissociation and misfolding.…”

Section: +mentioning

confidence: 90%

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

Pratt

Shin

Merz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Protein framework alterations in heritable Cu, Zn superoxide dismutase (SOD) mutants cause misassembly and aggregation in cells affected by the motor neuron disease ALS. However, the mechanistic relationship between superoxide dismutase 1 (SOD1) mutations and human disease is controversial, with many hypotheses postulated for the propensity of specific SOD mutants to cause ALS. Here, we experimentally identify distinguishing attributes of ALS mutant SOD proteins that correlate with clinical severity by applying solution biophysical techniques to six ALS mutants at human SOD hotspot glycine 93. A small-angle X-ray scattering (SAXS) assay and other structural methods assessed aggregation propensity by defining the size and shape of fibrillar SOD aggregates after mild biochemical perturbations. Inductively coupled plasma MS quantified metal ion binding stoichiometry, and pulsed dipolar ESR spectroscopy evaluated the Cu 2+ binding site and defined cross-dimer copper-copper distance distributions. Importantly, we find that copper deficiency in these mutants promotes aggregation in a manner strikingly consistent with their clinical severities. G93 mutants seem to properly incorporate metal ions under physiological conditions when assisted by the copper chaperone but release copper under destabilizing conditions more readily than the WT enzyme. Altered intradimer flexibility in ALS mutants may cause differential metal retention and promote distinct aggregation trends observed for mutant proteins in vitro and in ALS patients. Combined biophysical and structural results test and link copper retention to the framework destabilization hypothesis as a unifying general mechanism for both SOD aggregation and ALS disease progression, with implications for disease severity and therapeutic intervention strategies. Lou Gehrig's disease | small-angle X-ray scattering | protein aggregation | protein conformation | ESR spectroscopy A LS is a lethal degenerative disease of the human motor system (1). Opportunities for improved understanding and clinical intervention arose from the discovery that up to 23.5% of familial ALS cases and 7% of spontaneous cases are caused by mutations in the superoxide dismutase 1 (SOD1) gene encoding human Cu, Zn SOD (2-4). SOD is a highly conserved (5), dimeric, antioxidant metalloenzyme that detoxifies superoxide radicals (6, 7), but overexpression of SOD1 ALS mutants is sufficient to cause disease in mice (8). Misfolded and/or aggregated SOD species are deposited within mouse neuronal and glial inclusions (9, 10), even before symptoms appear (11,12). Although human familial ALS has a symptomatic phenotype indistinguishable from sporadic cases (13), individual SOD1 mutations can result in highly variable disease progression and penetrance (14,15).Many nongeneral mechanisms, including loss of activity or gain of function, were postulated to explain the roles of SOD mutants in ALS (3,(16)(17)(18)(19). Recently, however, an initial hypothesis proposing that SOD manifests disease symptoms by framework dest...

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Section: +mentioning

confidence: 90%

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

Pratt

Shin

Merz³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Subsequent studies by these and other investigators have shown that hSOD1 oxidized by long incubations with hydrogen peroxide, added in bolus or generated by other agents, undergoes major structural changes and non-amyloid aggregation resembling that observed in ALS (10,18,19,26). These structural modifications have been shown to occur downstream to the oxidation of His 80 and His 120 residues in the active site of hSOD1 (10). These oxidations are caused by Fenton chemistry, including that associated with the peroxidase activity of SOD1, in which the enzyme consumes modest amounts of hydrogen peroxide to become oxidized and inactivated (27).…”

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confidence: 82%

“…As is the case with other neurodegenerative diseases, protein misfolding and aggregation are hallmarks of ALS. A distinctive feature of ALS is that it displays amorphous protein aggregates instead of the amyloid aggregates characteristic of most protein aggregation diseases (9,10). SOD1 mutations are responsible for a small percentage of the familial cases of ALS (20%).…”

mentioning

confidence: 99%

“…The produced hSOD1-tryptophanyl radical (hSOD1-Trp 32 ⅐ ) decays to hSOD1-N-formylkynurenine and hSOD1-kynurenine (3) or reacts with another hSOD1-Trp 32 ⅐ to produce the covalent dimer cross-linked by a ditryptophan bond (hSOD1-Trp-Trp-hSOD1) (30). Apparently, the latter hSOD1 oxidation products are different from those produced in the absence of the bicarbonate buffer (10) and are likely specific for human and other simian SOD1s, which contain the Trp 32 residue. The involvement of the oxidation products of hSOD1-Trp 32 in triggering hSOD1 aggregation has been hypothesized (3) but not investigated.…”

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confidence: 99%

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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

Coelho

Iqbal

Linares

et al. 2014

Journal of Biological Chemistry

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“…Further illustrating the zinc hypothesis are results showing abatement of cell destruction by the addition of exogenous zinc and exacerbation by the addition of known zinc chelators. 38 These misfolded SOD1 mutants are increasingly becoming the target for drug therapy 39 due primarily to their speculated early involvement in a thorough and complex oxidative damage cascade. Monoclonal antibody experiments targeting these abnormally folded SOD1 mutants 40 have already been demonstrated in murine and human tissues.…”

Section: Cu/zn Superoxide Dismutase 1 (Sod1)mentioning

confidence: 99%

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

Sanford¹

2015

MJM

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Early Steps in Oxidation-Induced SOD1 Misfolding: Implications for Non-Amyloid Protein Aggregation in Familial ALS

Cited by 47 publications

References 84 publications

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

Aggregation propensities of superoxide dismutase G93 hotspot mutants mirror ALS clinical phenotypes

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

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

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