The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease)

Potter, Soshanna Zittin; Valentine, Joan Selverstone

doi:10.1007/s00775-003-0447-6

Cited by 57 publications

(48 citation statements)

References 32 publications

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“…In other words, the occupancy of one or both of the copper sites increases subunit affinity and the interactions in the beta-barrel to a maximum whereby dimer SOD1 behaves like a highly stable monomeric protein. Similar results are observed for natively metallated Cu 2 Zn 2 SOD1 which also melts in a single peak but at an astonishingly high temperature of 928C (54). While many studies have shown that the binding of zinc stabilizes SOD1 structure considerably, these results suggest that copper also plays an important role in strengthening SOD1 structure.…”

supporting

confidence: 71%

Aggregation of Copper–Zinc Superoxide Dismutase in Familial and Sporadic ALS

Chattopadhyay

Valentine

2009

Antioxidants & Redox Signaling

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Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by the selective death of motor neurons. While the most common form of ALS is sporadic and has no known cause, a small subset of cases is familial because of underlying genetic mutations. The best-studies example of familial ALS is that caused by mutations in the protein copper-zinc superoxide dismutase. The formation of SOD1-rich inclusions in the spinal cord is an early and prominent feature of SOD1-linked familial ALS in human patients and animal models of this disease. These inclusions have been shown to consist of SOD1-rich fibrils, suggesting that the conversion of soluble SOD1 into amyloid fibrils may play an important role in the etiology of familial ALS. SOD1 is also present in inclusions found in spinal cords of sporadic ALS patients, allowing speculations to arise regarding a possible involvement of SOD1 in the sporadic form of this disease. We here review the recent research on the significance, causes, and mechanisms of SOD1 fibril formation from a biophysical perspective.

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supporting

confidence: 71%

Aggregation of Copper–Zinc Superoxide Dismutase in Familial and Sporadic ALS

Chattopadhyay

Valentine

2009

Antioxidants & Redox Signaling

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139

124

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“…Successive loss of metal ions lowers the melting temperature until the completely demetallated (apo) dimeric form melts at 52°C. Reduction of the Cys-57-Cys-146 disulfide bond converts the dimeric apoprotein to the monomeric form and lowers the melting point further to 42°C (29). The monomeric disulfidereduced, metal-free form of SOD1 protein is the least stable form of SOD1 known to still maintain the ␤-barrel fold (30).…”

mentioning

confidence: 99%

The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation

Chattopadhyay

Nwadibia

Strong

et al. 2015

Journal of Biological Chemistry

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Aggregation of copper-zinc superoxide dismutase (SOD1) is a defining feature of familial ALS caused by inherited mutations in the sod1 gene, and misfolded and aggregated forms of wildtype SOD1 are found in both sporadic and familial ALS cases. Mature SOD1 owes its exceptional stability to a number of posttranslational modifications as follows: formation of the intramolecular disulfide bond, binding of copper and zinc, and dimerization. Loss of stability due to the failure to acquire one or more of these modifications is proposed to lead to aggregation in vivo. Previously, we showed that the presence of apo-, disulfide-reduced SOD1, the most immature form of SOD1, results in initiation of fibrillation of more mature forms that have an intact Cys-57-Cys-146 disulfide bond and are partially metallated. In this study, we examine the ability of each of the above post-translational modifications to modulate fibril initiation and seeded growth. Cobalt or zinc binding, despite conferring great structural stability, neither inhibits the initiation propensity of disulfide-reduced SOD1 nor consistently protects disulfide-oxidized SOD1 from being recruited into growing fibrils across wild-type and a number of ALS mutants. In contrast, reduction of the disulfide bond, known to be necessary for fibril initiation, also allows for faster recruitment during seeded amyloid growth. These results identify separate factors that differently influence seeded growth and initiation and indicate a lack of correlation between the overall thermodynamic stability of partially mature SOD1 states and their ability to initiate fibrillation or be recruited by a growing fibril. Familial amyotrophic lateral sclerosis (FALS)3 caused by mutations in the SOD1 gene shows similarities to other members of the large class of neurodegenerative disorders that are characterized by gradual aggregation of specific proteins and subsequent cell death in characteristic regions of the central nervous system. Some prominent examples are amyloid-␤ deposits in Alzheimer disease, ␣-synuclein and hyperphosphorylated Tau protein deposits in Parkinson disease, prion protein deposits in the transmissible spongiform encephalopathies, and huntingtin deposits in Huntington disease (1). In the case of SOD1-linked FALS, protein deposits have been identified in affected tissues from patients and from ALS-SOD1 transgenic mice consisting largely of aggregated copper,zinc superoxide dismutase protein (Cu,Zn-SOD, SOD1 protein).Our current understanding of this class of diseases is that the implicated proteins misfold, aggregate, and ultimately deposit as extracellular plaques or intracellular inclusions in the afflicted regions of the CNS. Although the exact structures contributing to these heterogeneous protein aggregates are unknown, such diseases are nevertheless usually referred to as "amyloid diseases" because fibrillar properties characteristic of cross-␤-sheet amyloid are often detected in them and because each of the isolated proteins implicated in causing disease shows a...

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“…The effects of fALS mutations on the normal enzyme activity, turnover, and folding of SOD1 vary considerably (7)(8)(9). In cell culture and in vitro models, enzyme activity ranges from undetectable to near normal (7, 10 -13); most mutations accelerate the rate of protein turnover (7,12); and many mutations increase the susceptibility of SOD1 to disulfide reduction (14).…”

mentioning

confidence: 99%

A Limited Role for Disulfide Cross-linking in the Aggregation of Mutant SOD1 Linked to Familial Amyotrophic Lateral Sclerosis

Karch

Borchelt

2008

Journal of Biological Chemistry

132

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One of the mechanisms by which mutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS) is proposed to involve the accumulation of detergentinsoluble, disulfide-cross-linked, mutant protein. Recent studies have implicated cysteine residues at positions 6 and 111 as critical in mediating disulfide cross-linking and promoting aggregation. In the present study, we used a panel of experimental and disease-linked mutations at cysteine residues of SOD1 (positions 6, 57, 111, and 146) in cell culture assays for aggregation to demonstrate that extensive disulfide cross-linking is not required for the formation of mutant SOD1 aggregates. Experimental mutants possessing only a single cysteine residue or lacking cysteine entirely were found to retain high potential to aggregate. Furthermore we demonstrate that aggregate structures in symptomatic SOD1-G93A mice can be dissociated such that they no longer sediment upon ultracentrifugation (i.e. appear soluble) under relatively mild conditions that leave disulfide bonds intact. Similar to other recent work, we found that cysteines 6 and 111, particularly the latter, play interesting roles in modulating the aggregation of human SOD1. However, we did not find that extensive disulfide cross-linking via these residues, or any other cysteine, is critical to aggregate structure. Instead we suggest that these residues participate in other features of the protein that, in some manner, modulate aggregation.Amyotrophic lateral sclerosis (ALS), 2 a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons, typically presents with unknown etiology (sporadic ALS). Rarely cases of ALS exhibit dominant patterns of inheritance (familial ALS), and a subset of these cases are caused by mutations in SOD1 (1). More than 100 mutations in SOD1 have been identified in cases of fALS. The majority of these fALS-linked SOD1 mutations are point mutations. A subset of fALS mutations causes shifts in the reading frame or introduces early termination codons, resulting in the production of C-terminally truncated proteins.SOD1 is a metalloenzyme responsible for metabolizing oxygen radicals that are produced during normal cellular metabolism. The active enzyme is a homodimer of two 153-amino acid subunits with each subunit containing eight ␤-strands, an active site that binds copper, a binding site for zinc, an electrostatic loop that directs the substrate into the active site, and an intramolecular disulfide bond between cysteine 57 and cysteine 146 (2). Together these structural aspects of SOD1 produce an extremely stable protein, retaining its structure in 1% SDS and 8 M urea (3). SOD1 is primarily located in the cytosol but has been found at lower levels in nuclei, peroxisomes, and mitochondria (4 -6).The effects of fALS mutations on the normal enzyme activity, turnover, and folding of SOD1 vary considerably (7-9). In cell culture and in vitro models, enzyme activity ranges from undetectable to near normal (7, 10 -13); most muta...

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The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease)

Cited by 57 publications

References 32 publications

Aggregation of Copper–Zinc Superoxide Dismutase in Familial and Sporadic ALS

Aggregation of Copper–Zinc Superoxide Dismutase in Familial and Sporadic ALS

The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation

A Limited Role for Disulfide Cross-linking in the Aggregation of Mutant SOD1 Linked to Familial Amyotrophic Lateral Sclerosis

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