Aggregate Formation in Cu,Zn Superoxide Dismutase-related Proteins

Son, Marjatta; Cloyd, C. Dyan; Rothstein, Jeffrey D.; Rajendran, Bhagya; Elliott, Jeffrey L.

doi:10.1074/jbc.m211698200

Cited by 40 publications

(33 citation statements)

References 39 publications

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“…Although the function of the amino terminal half of the mature EC-SOD is unclear, amino acid residues 96-193 show a high level of sequence homology to CuZn-SOD, and also contain the critical amino acids for catalytic activity. There was no sequence homology between Mn-SOD and EC-SOD (10).…”

Section: Introductionmentioning

confidence: 95%

“…The human EC-SOD gene, which is located on chromosome 4p16.3-q21, contains three exons and two introns. A gene distinct from CuZn-SOD is responsible for encoding human EC-SOD, which is composed of 240 amino acids and harbors an 18-peptide segment that targets the protein to the extracellular compartment (8,10). Although the function of the amino terminal half of the mature EC-SOD is unclear, amino acid residues 96-193 show a high level of sequence homology to CuZn-SOD, and also contain the critical amino acids for catalytic activity.…”

Section: Introductionmentioning

confidence: 99%

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A Haplotype-Based Case-Control Study Examining Human Extracellular Superoxide Dismutase Gene and Essential Hypertension

et al. 2008

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It has been reported that oxidative stress is involved in the pathophysiology of essential hypertension (EH),which is a multifactorial disorder. Extracellular superoxide dismutase (EC-SOD) protects the human body from oxidative stress by converting the toxic superoxide anion (O2 -) into less toxic hydrogen peroxide (H2O2). In EC-SOD knockout mice, blood pressure was reported to be significantly higher than that seen in wild-type mice. The aim of this study was thus to investigate the relationship between EH and the human EC-SOD gene by using single-nucleotide polymorphisms (SNPs) in a haplotype-based case-control study.We selected 6 SNPs within the human EC-SOD gene (rs13306703, rs699473, rs699474, rs17881426, rs2536512 and rs1799895), and then performed case-control studies in 243 EH patients and 251 age-matched normotensive (NT) subjects. In Japanese subjects, no heterogeneity was found for rs699474, and no significant differences were observed between the EH and NT groups for the overall distribution of the genotypes or the alleles for each of the SNPs. However, in the haplotype-based case-control study that used rs13306703 and rs2536512, significant differences were observed in the overall distribution (

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Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

A Haplotype-Based Case-Control Study Examining Human Extracellular Superoxide Dismutase Gene and Essential Hypertension

et al. 2008

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“…Western blots and immunohistochemistry were done as previously described (31). The primary antibodies are listed in SI Text.…”

Section: Methodsmentioning

confidence: 99%

Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology

Son¹,

Puttaparthi²,

Kawamata

et al. 2007

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

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143

164

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Cu, Zn superoxide dismutase (SOD1) has been detected within spinal cord mitochondria of mutant SOD1 transgenic mice, a model of familial ALS. The copper chaperone for SOD1 (CCS) provides SOD1 with copper, facilitates the conversion of immature apo-SOD1 to a mature holoform, and influences in yeast the cytosolic/ mitochondrial partitioning of SOD1. To determine how CCS affects G93A-SOD1-induced disease, we generated transgenic mice overexpressing CCS and crossed them to G93A-SOD1 or wild-type SOD1 transgenic mice. Both CCS transgenic mice and CCS/wild-type-SOD1 dual transgenic mice are neurologically normal. In contrast, CCS/G93A-SOD1 dual transgenic mice develop accelerated neurological deficits, with a mean survival of 36 days, compared with 242 days for G93A-SOD1 mice. Immuno-EM and subcellular fractionation studies on the spinal cord show that G93A-SOD1 is enriched within mitochondria in the presence of CCS overexpression. Our results indicate that CCS overexpression in G93A-SOD1 mice produces severe mitochondrial pathology and accelerates disease course.amyotrophic lateral sclerosis ͉ motor neuron ͉ neurodegeneration ͉ transgenic ͉ aggregation

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“…Mitochondria were isolated from dissected spinal cords by using Sigma mitochondria isolation kit (Sigma), and Western blots were done as previously described (24). The experiments were performed using the following primary antibodies: mouse anti-TIM23, 1:2000 (BD Transduction Laboratories); rabbit anti-TOM20, 0.2 g/ml (Santa Cruz Biotechnology, Inc.), rabbit anti-MnSOD 0.2 g/ml (StressGen); mouse anti-COX1 subunit, 1 g/ml (clone 1D6) (Molecular Probes, Inc., Eugene, OR); mouse anti-COX5b subunit, 1 g/ml (clone 16H12) (Molecular Probes); mouse anti-complex I NDUFB8 subunit, 0.5 g/ml (Mitosciences); goat anti-complex I ND2 subunit, 1 g/ml (Santa Cruz Biotechnology); mouse anti-complex II Fp70 subunit, 0.1 g/ml (Mitosciences); mouse anti-complex III core 1 subunit, 0.5 g/ml (Mitosciences); mouse anti-complex V ATPase ␤ subunit, 0.5 g/ml (Mitosciences).…”

Section: CMmentioning

confidence: 99%

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

Son

Leary

Romain

et al. 2008

Journal of Biological Chemistry

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G93A SOD1 transgenic mice overexpressing CCS protein develop an accelerated disease course that is associated with enhanced mitochondrial pathology and increased mitochondrial localization of mutant SOD1. Because these results suggest an effect of mutant SOD1 on mitochondrial function, we assessed the enzymatic activities of mitochondrial respiratory chain complexes in the spinal cords of CCS/G93A SOD1 and control mice. CCS/G93A SOD1 mouse spinal cord demonstrates a 55% loss of complex IV (cytochrome c oxidase) activity compared with spinal cord from age-matched non-transgenic or G93A SOD1 mice. In contrast, CCS/G93A SOD1 spinal cord shows no reduction in the activities of complex I, II, or III. Blue native gel analysis further demonstrates a marked reduction in the levels of complex IV but not of complex I, II, III, or V in spinal cords of CCS/G93A SOD1 mice compared with nontransgenic, G93A SOD1, or CCS/WT SOD1 controls. With SDS-PAGE analysis, spinal cords from CCS/G93A SOD1 mice showed significant decreases in the levels of two structural subunits of cytochrome c oxidase, COX1 and COX5b, relative to controls. In contrast, CCS/G93A SOD1 mouse spinal cord showed no reduction in levels of selected subunits from complexes I, II, III, or V. Heme A analyses of spinal cord further support the existence of cytochrome c oxidase deficiency in CCS/G93A SOD1 mice. Collectively, these results establish that CCS/G93A SOD1 mice manifest an isolated complex IV deficiency which may underlie a substantial part of mutant SOD1-induced mitochondrial cytopathy.

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Aggregate Formation in Cu,Zn Superoxide Dismutase-related Proteins

Cited by 40 publications

References 39 publications

A Haplotype-Based Case-Control Study Examining Human Extracellular Superoxide Dismutase Gene and Essential Hypertension

A Haplotype-Based Case-Control Study Examining Human Extracellular Superoxide Dismutase Gene and Essential Hypertension

Overexpression of CCS in G93A-SOD1 mice leads to accelerated neurological deficits with severe mitochondrial pathology

Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein

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