Disease relevance of SOD1

• Single-site mutants in the Cu,Zn superoxide dismutase (SOD) gene (SOD1) occur in patients with the fatal neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS) [1].
• Mutation-induced aggregation of the dimeric enzyme Cu, Zn superoxide dismutase 1 (SOD1) has been implicated in the familial form of the disease amyotrophic lateral sclerosis, but the mechanism of aggregation is not known [2].
• CONCLUSION: The upregulation of proinflammatory factors during early presymptomatic stages as well as the expansion of immune activation as disease progresses in mutant SOD1 transgenic mice suggest that immune-inflammatory mechanisms could contribute to disease progression [3].
• This observation is of relevance to understanding brain deficits in Down syndrome, as SOD1 is encoded on chromosome 21 [4].
• This provides further evidence for an involvement of proteasome impairment in the toxicity of mutant SOD1 [5].
• These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders [6].
• These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis [7].
• Heme A analyses of spinal cord further support the existence of cytochrome c oxidase deficiency in CCS/G93A SOD1 mice [8].

Psychiatry related information on SOD1

• Ten of the features could be assigned to the region flanked by genes APP and SOD1: six facial features, transverse palmar crease, arthrogryposis-like symptoms, hypertonia, and contribution to mental retardation [9].
• Transgenic mouse strains overexpressing wild-type human SOD1 (Tg-SOD1) were shown to have mitochondrial swelling, vacuolization, or learning and memory deficits and are widely used for biochemical, genetic, and cognitive studies; this, along with the advent of advanced proteomic methods, made us investigate protein expression in hippocampus [4].
• We investigated the substantia nigra (SN) in MND cases; two cases of motor neurone disease inclusion body (MND-IB) dementia, six cases of DMND, 14 cases of MND (including one case from Guam and two cases of familial SOD1 mutation), four cases of Parkinson's disease (PD), and 10 cases of age-matched normal controls [10].
• Having had success in extending the life of mice with a transgene for amyotropic lateral sclerosis (SOD1) mice and Huntington's disease (Hdexon1), we administered megadoses of human umbilical cord blood mononuclear cells to mice with Alzheimer's disease [11].
• In order to dissect genetic causes of the syndrome, hemizygous human wild-type SOD1 transgenic mice were compared to FVB/N non-transgenic controls at 3 months of age in the SHIRPA primary screen of neurologic function as well as in tests of motor activity and coordination [12].

High impact information on SOD1

• Over 100 different mutations have been identified in the sod1 genes of patients diagnosed with the familial form of amyotrophic lateral sclerosis (fALS) [13].
• PR is a symmetric homodimer whose subunits contribute to formation of a single active site [14].
• Both quasisymmetric heterodimers resemble the symmetric Max homodimer, albeit with marked structural differences in the coiled-coil leucine zipper regions that explain preferential homo- and heteromeric dimerization of these three evolutionarily related DNA-binding proteins [15].
• Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33 [16].
• HsMAD1 functions as a homodimer [17].

Chemical compound and disease context of SOD1

• To test the hypothesis that the toxicity of mutant SOD1 originates in Cu(2+)-mediated formation of toxic radicals, we generated transgenic mice that express human SOD1 that encodes disease-linked mutations at two of the four histidine residues that are crucial for the coordinated binding of copper (H46R/H48Q) [18].
• Approximately 10% of all familial cases of amyotrophic lateral sclerosis (fALS) are linked to mutations in the SOD1 gene, which encodes the copper/zinc superoxide dismutase (CuZnSOD) [19].
• In this study, we have challenged with Abeta, either in the presence or in the absence of 17beta-estradiol, differentiated human neuroblastoma SH-SY5Y cells (named line SH) and the same line overexpressing anti-oxidant enzyme superoxide dismutase 1 (SOD1; named line WT) [20].
• We further demonstrate that ebselen, an anti-oxidant drug already safely used in human studies and that acts as a Prx mimic, is able to ameliorate the toxicity of mutant SOD1 in our cell-culture model [21].
• The purpose of this study was to investigate the activities of SOD-1 and glutathione peroxidase (GSH-Px) enzymes and the levels of their cofactors zinc (Zn), copper (Cu) and selenium (Se) in plasma of 20 Down syndrome patients [22].

Biological context of SOD1

• Complete screening of the SOD1 coding region revealed that the mutation Ala4 to Val in exon 1 was the most frequent one; mutations were identified in exons 2, 4, and 5 but not in the active site region formed by exon 3 [1].
• "Sporadic" motoneuron disease due to familial SOD1 mutation with low penetrance [23].
• Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery [24].
• Molecular mapping of 21 features associated with partial monosomy 21: involvement of the APP-SOD1 region [9].
• A late event in the stress-induced molecular sequence was the induction of SOD1, catalase, and HSP27 coinciding with development of the fully senescent phenotype [25].

Anatomical context of SOD1

• Such endothelial dysfunction was not found in transgenic mice expressing both APP and superoxide dismutase-1 (SOD1) or in APP transgenics in which SOD was topically applied to the cerebral cortex [26].
• In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed [24].
• Deficient S-nitrosylation is particularly prominent in the mitochondria of cells expressing SOD1 mutants [27].
• In vivo, alphaB-crystallin immunoreactivity was most abundant in oligodendrocytes and up-regulated in astrocytes of symptomatic mice; neither of these cell-types accumulated mutant SOD1 immunoreactivity [28].
• Thus, our results suggest that an adverse interaction among misfolded SOD1, NEDL1, translocon-associated protein-delta, and Dishevelled-1 forms a ubiquitinated protein complex that is included in potentially cytotoxic protein aggregates and that mutually affects their functions, leading to motor neuron death in FALS [29].

Associations of SOD1 with chemical compounds

• Taken together, our findings suggest that caspase-3 cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate uptake in mutant SOD1-linked ALS [30].
• The monounsaturated FA, oleic acid, directly bound to SOD1 and was characterized by a solid-phase FA binding assay using oleate-Sepharose [31].
• Mutations of Cu/Zn superoxide dismutase 1 (SOD1), a metalloenzyme catalyzing the conversion of superoxide anion to hydrogen peroxide (H(2)O(2)), are linked to motor neuron degeneration [4].
• Bicarbonate anion (HCO3-) enhances the covalent aggregation of hSOD1 mediated by the SOD1 peroxidase-dependent formation of carbonate radical anion (CO3*-), a potent and selective oxidant [32].
• SOD1, CAT and GST activity and glutathione content, which remained at similar levels in the 2 cell lines for all times studied, appeared unrelated to the differentiation process [33].
• We show that in mammalian cells mutant SOD1 interacts preferentially with the mitochondrial form of KARS (mitoKARS) [34].
• Cysteine 111 glutathionylation promotes SOD1 monomer formation, a necessary initiating step in SOD1 aggregation, by causing a 2-fold increase in the K(d) [35].

Physical interactions of SOD1

• Overexpression of X11alpha inhibited SOD1 activity in transfected Chinese hamster ovary cells which suggests that X11alpha binding to CCS is inhibitory to SOD1 activation [36].
• Since Jun homodimers cannot bind to AP-1 sites in a preferred orientation, the effects of the orientations of nonconsensus AP-1 sites on the stabilities of Jun-Jun-NFAT1 complexes are likely to be due to asymmetric conformational changes in the two subunits of the homodimer [37].
• Human p53 binds DNA as a protein homodimer but monomeric variants retain full transcription transactivation activity [38].
• Commentary on: return of the cycad hypothesis - does the amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC) of Guam have new implications for global health [39]?
• Although E2F1 can bind DNA as a homodimer and increase promoter activity, optimal DNA-binding and transcriptional activity occurs in the heterodimeric form [40].

Enzymatic interactions of SOD1

• CCS also oxidizes an intrasubunit disulfide in SOD1 [41].
• CD69 is a phosphorylated disulfide-linked homodimer that appears on the surface of human T, B cells and thymocytes in the early steps of activation; its molecular mass is 28 to 34 kDa under reducing conditions [42].
• This implies a conserved role for N-domain dimerization, which might include influencing interactions with cytokine receptors, favoring homodimer formation or accelerating formation of the phosphorylated STAT dimer [43].
• Plant acetohydroxy acid isomeroreductase is a stable homodimer which catalyzes in the presence of magnesium an alkyl migration followed by a NADPH-dependent reduction [44].

Regulatory relationships of SOD1

• Overexpression of Cu/Zn superoxide dismutase 1 (SOD1) in monocytes blocks reactive oxygen species-induced inhibition of cell growth and apoptosis and renders cells resistant to the toxic effect of tumor necrosis factor (TNF)-alpha, suggesting that TNF-alpha represses the SOD1 gene in these cells [45].
• We therefore conclude that mutant SOD1 overexpression promotes neither Abeta toxicity nor brain accumulation in these ALS models [46].
• Hsp70 and Hsp40 improve neurite outgrowth and suppress intracytoplasmic aggregate formation in cultured neuronal cells expressing mutant SOD1 [47].
• Transient transfection and in vitro transcription assays indicate that ATF3 represses transcription as a homodimer; however, ATF3 can activate transcription when coexpressed with its heterodimeric partners or other proteins [48].
• As a result of this physical interaction, binding of h-TR beta 1 to its hormone response elements either as homodimer or as a heterodimer with the retinoic X receptor was inhibited by p53 in a concentration-dependent manner [49].

Other interactions of SOD1

• RESULTS: ALS2-deficient mice demonstrated progressive axonal degeneration in the lateral spinal cord that is also prominent in mutant SOD1 mice [50].
• Transgenic mice overexpressing the non-mutated SOD1 gene did not overexpress S100A6, although glial fibrillary associated protein astrogliosis was seen [51].
• Total SOD activity was fairly constant, whereas the ratio SOD2/SOD1 was much lower in TF than in NF [52].
• Exercise-induced eNOS expression is transient and reversible and regulated by factors such as angiogenesis, arteriogenesis and antioxidative effects including upregulation of superoxide dismutases (SOD1, SOD3) and downregulation of NAD(P)H oxidase, which likely blunts the effects of oxidative stress [53].
• This suggests that the decreased expression of PRDX2 may contribute to the altered redox state in DS at levels comparable to that of the increased expression of SOD1 [54].

Analytical, diagnostic and therapeutic context of SOD1

• Here, we show that the increased denitrosylase activity of SOD1 mutants leads to an aberrant decrease in intracellular protein and peptide S-nitrosylation in cell and animal models of ALS [27].
• These cells survived up to 11 weeks following transplantation into the lumbar spinal cord of rats overexpressing the G93A SOD1 mutation (SOD1 (G93A)) [55].
• Hippocampal tissues of wild-type, hemizygous, and homozygous Tg-SOD1 mice were isolated and used for two-dimensional gel electrophoresis with subsequent matrix-assisted laser desorption/ionization-time of flight identification [4].
• The amounts of SOD1, SOD2 and CAT immunoreactive proteins, estimated by Western blotting, appeared to be correlated to their respective enzymatic activities [33].
• Using microdialysis in vivo, we tested the effects of the glutamate transport inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (PDC) and of 4-aminopyridine (4-AP), which stimulates glutamate release from nerve endings, in the hippocampus and motor cortex of wild type (WT) and transgenic SOD1/G93A mice, an established model of FALS [56].

References