スーパーオキシドジスムターゼ1

関: superoxide dismutase 1

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/06 21:17:45」(JST)

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Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene, located on chromosome 21. SOD1 is one of three human superoxide dismutases. ^[1] ^[2]

Function[edit]

SOD1 binds copper and zinc ions and is one of three superoxide dismutases responsible for destroying free superoxide radicals in the body. The encoded isozyme is a soluble cytoplasmic and mitochondrial intermembrane space protein, acting as a homodimer to convert naturally occurring, but harmful, superoxide radicals to molecular oxygen and hydrogen peroxide.^[3]

Clinical significance[edit]

In one study, deletions in the gene were reported in two familial cases of keratoconus.^[4]

Mice lacking SOD1 have increased age-related muscle mass loss (sarcopenia), early development of cataracts, macular degeneration, thymic involution, hepatocellular carcinoma, and shortened lifespan.^[5]

Amyotrophic lateral sclerosis (Lou Gehrig's disease)[edit]

Mutations (over 150 identified to date) in this gene have been linked to familial amyotrophic lateral sclerosis.^[6]^[7] However, several pieces of evidence also show that wild-type SOD1, under conditions of cellular stress, is implicated in a significant fraction of sporadic ALS cases, which represent 90% of ALS patients. ^[8] The most frequent mutation are A4V (in the U.S.A.) and H46R (Japan). The most studied ALS mouse model is G93A. Rare transcript variants have been reported for this gene.^[3]

Virtually all known ALS-causing SOD1 mutations act in a dominant fashion; a single mutant copy of the SOD1 gene is sufficient to cause the disease. The exact molecular mechanism (or mechanisms) by which SOD1 mutations cause disease are unknown. It appears to be some sort of toxic gain of function, as many disease-associated SOD1 mutants (including G93A and A4V) retain enzymatic activity and Sod1 knockout mice do not develop ALS (although they do exhibit a strong age-dependent distal motor neuropathy).

A4V mutation[edit]

A4V (alanine at codon 4 changed to valine) is the most common ALS-causing mutation in the U.S. population, with approximately 50% of SOD1-ALS patients carrying the A4V mutation.^[9]^[10]^[11] Approximately 10 percent of all U.S. familial ALS cases are caused by heterozygous A4V mutations in SOD1. The mutation is rarely if ever found outside the Americas.

It was recently estimated that the A4V mutation occurred 540 generations (~12,000 years) ago. The haplotype surrounding the mutation suggests that the A4V mutation arose in the Asian ancestors of native Americans, who reached the Americas through the Bering Strait.^[12]

The A4V mutant belongs to the WT-like mutants. Patients with A4V mutations exhibit variable age of onset, but uniformly very rapid disease course, with average survival after onset of 1.4 years (versus 3–5 years with other dominant SOD1 mutations, and in some cases such as H46R, considerably longer). This survival is considerably shorter than non-mutant SOD1 linked ALS.

H46R mutation[edit]

H46R (Histidine at codon 46 changed to Arginine) is the most common ALS-causing mutation in the Japanese population, with approximately 40% of Japanese SOD1-ALS patients carrying this mutation. H46R causes a profound loss of copper binding in the active site of SOD1, and as such, H46R is enzymatically inactive. The disease course of this mutation is extremely long, with the typical time from onset to death being over 15 years.^[13] Mouse models with this mutation do not exhibit the classical mitochondrial vacuolation pathology seen in G93A and G37R ALS mice and unlike G93A mice, defeciency of the major mitochondrial antioxidant enzyme, SOD2, has no effect on their disease course.^[13]

G93A mutation[edit]

G93A (glycine 93 changed to alanine) is a comparatively rare mutation, but has been studied very intensely as it was the first mutation to be modeled in mice. G93A is a pseudo-WT mutation that leaves the enzyme activity intact.^[11] Because of the ready availability of the G93A mouse from Jackson lab, many studies of potential drug targets and toxicity mechanisms have been carried out in this model. At least one private research institute ( ALS Therapy Development Institute ) is conducting large scale drug screens exclusively in this mouse model. Whether findings are specific for G93A or applicable to all ALS causing SOD1 mutations is at present unknown. It has been argued that certain pathological features of the G93A mouse are due to overexpression artefacts, specifically those relating to mitochondrial vacuolation (the G93A mouse commonly used from the Jackson lab has over 20 copies of the human SOD1 gene).^[14] At least one study has found that certain features of pathology are idiosyncratic to G93A and not extrapolatable to all ALS causing mutations.^[13]

Interactions[edit]

SOD1 has been shown to interact with CCS^[15] and Bcl-2.^[16] ^[17] ^[18] ^[19]

References[edit]

^ Milani P, Gagliardi S, Cova E, Cereda C (2011). "SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS.". Neurol Res Int. 2011: 458427. doi:10.1155/2011/458427. PMC 3096450. PMID 21603028.
^ Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX (March 1993). "Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis". Nature 362 (6415): 59–62. doi:10.1038/362059a0. PMID 8446170.
^ ^a ^b "Entrez Gene: SOD1 superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))".
^ Udar N, Atilano SR, Brown DJ, Holguin B, Small K, Nesburn AB, Kenney MC (August 2006). "SOD1: a candidate gene for keratoconus". Invest. Ophthalmol. Vis. Sci. 47 (8): 3345–51. doi:10.1167/iovs.05-1500. PMID 16877401.
^ Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (August 2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558.
^ Conwit RA (December 2006). "Preventing familial ALS: a clinical trial may be feasible but is an efficacy trial warranted?". J. Neurol. Sci. 251 (1-2): 1–2. doi:10.1016/j.jns.2006.07.009. PMID 17070848.
^ Al-Chalabi A, Leigh PN (August 2000). "Recent advances in amyotrophic lateral sclerosis". Curr. Opin. Neurol. 13 (4): 397–405. doi:10.1097/00019052-200008000-00006. PMID 10970056.
^ Gagliardi S, Cova E, Davin A, Guareschi S, Abel K, Alvisi E, Laforenza U, Ghidoni R, Cashman JR, Ceroni M, Cereda C (August 2010). "SOD1 mRNA expression in sporadic amyotrophic lateral sclerosis". Neurobiol. Dis. 39 (2): 198–203. doi:10.1016/j.nbd.2010.04.008. PMID 20399857.
^ Rosen DR, Bowling AC, Patterson D, Usdin TB, Sapp P, Mezey E, McKenna-Yasek D, O'Regan J, Rahmani Z, Ferrante RJ (June 1994). "A frequent ala 4 to val superoxide dismutase-1 mutation is associated with a rapidly progressive familial amyotrophic lateral sclerosis". Hum. Mol. Genet. 3 (6): 981–7. doi:10.1093/hmg/3.6.981. PMID 7951249.
^ Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, Schoenfeld DA, Hosler BA, Horvitz HR, Brown RH (February 1997). "Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis". Ann. Neurol. 41 (2): 210–21. doi:10.1002/ana.410410212. PMID 9029070.
^ ^a ^b Valentine JS, Hart PJ (April 2003). "Misfolded CuZnSOD and amyotrophic lateral sclerosis". Proc. Natl. Acad. Sci. U.S.A. 100 (7): 3617–22. doi:10.1073/pnas.0730423100. PMC 152971. PMID 12655070.
^ Broom WJ, Johnson DV, Auwarter KE, Iafrate AJ, Russ C, Al-Chalabi A, Sapp PC, McKenna-Yasek D, Andersen PM, Brown RH (January 2008). "SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia". Neurosci. Lett. 430 (3): 241–5. doi:10.1016/j.neulet.2007.11.004. PMID 18055113.
^ ^a ^b ^c Muller FL, Liu Y, Jernigan A, Borchelt D, Richardson A, Van Remmen H (September 2008). "MnSOD deficiency has a differential effect on disease progression in two different ALS mutant mouse models". Muscle Nerve 38 (3): 1173–83. doi:10.1002/mus.21049. PMID 18720509.
^ Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brännström T, Rehnmark A, Marklund SL (April 2006). "Overloading of stable and exclusion of unstable human superoxide dismutase-1 variants in mitochondria of murine amyotrophic lateral sclerosis models". J. Neurosci. 26 (16): 4147–54. doi:10.1523/JNEUROSCI.5461-05.2006. PMID 16624935.
^ Casareno RL, Waggoner D, Gitlin JD (September 1998). "The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase". J. Biol. Chem. 273 (37): 23625–8. doi:10.1074/jbc.273.37.23625. PMID 9726962.
^ Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH (July 2004). "Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria". Neuron 43 (1): 19–30. doi:10.1016/j.neuron.2004.06.021. PMID 15233914.
^ Cova E, Ghiroldi A, Guareschi S, Mazzini G, Gagliardi S, Davin A, Bianchi M, Ceroni M, Cereda C (October 2010). "G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis". Cell Signal 22 (10): 1477–1484. doi:10.1016/j.cellsig.2010.05.016. PMID 20561900.
^ Cereda C, Cova E, Di Poto C, Galli A, Mazzini G, Corato M, Ceroni M (November 2006). "Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral sclerosis patients: toxic or protective role?". Neurological Sciences 27 (5): 312–316. doi:10.1007/s10072-006-0702-z. PMID 17122939.
^ Emanuela Cova, Cristina Cereda, Alberto Galli, Daniela Curti, Chiara Finotti, Cristina Di Poto, Manuel Corato, Giuliano Mazzini, Mauro Ceroni (May 2006). "Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients". Neuroscience Letters 399 (3): 186–190. doi:10.1016/j.neulet.2006.01.057. PMID 16495003.

UpToDate Contents

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1. 家族性筋萎縮性側索硬化症 familial amyotrophic lateral sclerosis
2. 酸素毒性 oxygen toxicity
3. 心不全における酸化ストレスの役割 role of oxidative stress in heart failure
4. 内皮細胞機能不全 endothelial dysfunction
5. ベーチェット病の病因 pathogenesis of behcets disease

English Journal

Improving the knowledge of amyotrophic lateral sclerosis genetics: novel SOD1 and FUS variants.

Bertolin C1, D'Ascenzo C2, Querin G2, Gaiani A2, Boaretto F1, Salvoro C1, Vazza G1, Angelini C2, Cagnin A2, Pegoraro E2, Sorarù G3, Mostacciuolo ML4.Author information 1Laboratory of Human Genetics, Department of Biology, University of Padova, Padova, Italy.2Department of Neurosciences, University of Padova, Padova, Italy.3Department of Neurosciences, University of Padova, Padova, Italy. Electronic address: gianni.soraru@unipd.it.4Laboratory of Human Genetics, Department of Biology, University of Padova, Padova, Italy. Electronic address: marialuisa.mostacciuolo@unipd.it.AbstractAmyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients with sporadic ALS, 46 patients with familial ALS (FALS), and 73 patients affected with FTD, all originating from the northeastern part of Italy. C9ORF72 pathogenic expansion was found on 22% of familial ALS, 5% of sporadic ALS, and 14% of FTD patients, resulting the most frequently genetic determinant in our cohort. Sequence analysis of ALS cohort identified 2 novel variants on SOD1 (p.Glu41Gly) and FUS (p.Gly496Glyfs*31). Interestingly, the single base deletion on FUS was observed in an homozygous state, suggesting a recessive pattern of inheritance. No point mutations were identified on FTD cohort. Although useful to direct genetic testing, this study results expand the current knowledge of ALS genetics.
Neurobiology of aging.Neurobiol Aging.2014 May;35(5):1212.e7-1212.e10. doi: 10.1016/j.neurobiolaging.2013.10.093. Epub 2013 Oct 29.
Amyotrophic lateral sclerosis (ALS) is as an adult-onset neurodegenerative disorder involving both upper and lower motor neurons. About 5% of all cases exhibit signs of frontotemporal degeneration (FTD). We established the mutation frequency of C9ORF72, SOD1, TARDBP, and FUS genes in 307 patients wi
PMID 24325798

Characterization of thoracic motor and sensory neurons and spinal nerve roots in canine degenerative myelopathy, a potential disease model of amyotrophic lateral sclerosis.

Morgan BR, Coates JR, Johnson GC, Shelton GD, Katz ML.Author information Department of Biological Sciences, University of Missouri, Columbia, Missouri.AbstractCanine degenerative myelopathy (DM) is a progressive, adult-onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general proprioceptive ataxia and spastic upper motor neuron paresis in pelvic limbs, which progress to flaccid tetraplegia and dysphagia. The purpose of this study was to characterize DM as a potential disease model for ALS. We previously reported that intercostal muscle atrophy develops in dogs with advanced-stage DM. To determine whether other components of the thoracic motor unit (MU) also demonstrated morphological changes consistent with dysfunction, histopathologic and morphometric analyses were conducted on thoracic spinal motor neurons (MNs) and dorsal root ganglia (DRG) and in motor and sensory nerve root axons from DM-affected boxers and Pembroke Welsh corgis (PWCs). No alterations in MNs or motor root axons were observed in either breed. However, advanced-stage PWCs exhibited significant losses of sensory root axons, and numerous DRG sensory neurons displayed evidence of degeneration. These results indicate that intercostal muscle atrophy in DM is not preceded by physical loss of the motor neurons innervating these muscles, nor of their axons. Axonal loss in thoracic sensory roots and sensory neuron death suggest that sensory involvement may play an important role in DM disease progression. Further analysis of the mechanisms responsible for these morphological findings would aid in the development of therapeutic intervention for DM and some forms of ALS. © 2013 Wiley Periodicals, Inc.
Journal of neuroscience research.J Neurosci Res.2014 Apr;92(4):531-41. doi: 10.1002/jnr.23332. Epub 2013 Dec 21.
Canine degenerative myelopathy (DM) is a progressive, adult-onset, multisystem degenerative disease with many features in common with amyotrophic lateral sclerosis (ALS). As with some forms of ALS, DM is associated with mutations in superoxide dismutase 1 (SOD1). Clinical signs include general propr
PMID 24375814

Delineating the relationships among the formation of reactive oxygen species, cell membrane instability and innate autoimmunity in intestinal reperfusion injury.

Lee H1, Ko EH1, Lai M2, Wei N2, Balroop J3, Kashem Z1, Zhang M4.Author information 1Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States.2Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Biomedical Sciences, Long Island University, Brookville, NY 11548, United States.3Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Chemical and Biomolecular Engineering, NYU-Polytechnic Institute, Brooklyn, NY 11201, United States.4Department of Anesthesiology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States; Department of Cell Biology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, United States. Electronic address: ming.zhang@downstate.edu.AbstractAcute intestinal ischemia is a medical emergency with a high mortality rate, attesting to the need for a better understanding of its pathogenesis and the development of effective therapies. The goal of this study was to delineate the relationships among intracellular and extracellular events in intestinal ischemia/reperfusion (I/R) injury, particularly the formation of reactive oxygen species (ROS), cell membrane instability associated with lipid peroxidation and the innate autoimmune response mediated by natural IgM and complement. A murine model of natural IgM-mediated intestinal I/R was used. Mice overexpressing anti-oxidant enzyme SOD1 were found to have significantly reduced intestinal tissue damage and complete blockage of IgM-mediated complement activation compared with WT controls. To determine if cell membrane instability was an event intermediate between ROS formation and natural IgM-mediated innate autoimmune response, the cell membrane stabilizer (trehalose) was administered to WT mice prior to the induction of intestinal ischemia. Treatment with trehalose significantly protected animals from I/R injury and inhibited IgM-mediated complement activation although it did not prevent membrane lipid peroxidation. These data indicate that in normal mice subjected to I/R injury, intracellular ROS formation is an event upstream of the lipid peroxidation which results in cell membrane instability. The membrane instability leads to an innate autoimmune response by natural IgM and complement. Trehalose, a nontoxic disaccharide tolerated well by animals and humans, has promise as a protective agent for patients with medical conditions related to acute intestinal ischemia.
Molecular immunology.Mol Immunol.2014 Apr;58(2):151-9. doi: 10.1016/j.molimm.2013.11.012. Epub 2013 Dec 22.
Acute intestinal ischemia is a medical emergency with a high mortality rate, attesting to the need for a better understanding of its pathogenesis and the development of effective therapies. The goal of this study was to delineate the relationships among intracellular and extracellular events in inte
PMID 24365749

Japanese Journal

Anti-Aging Effects of Phloridzin, an Apple Polyphenol, on Yeast via the SOD and Sir2 Genes

XIANG Lan,SUN Kaiyue,LU Jun,WENG Yufang,TAOKA Akiko,SAKAGAMI Youji,QI Jianhua
Bioscience, biotechnology, and biochemistry 75(5), 854-858, 2011-05-23
… Further, SOD1, SOD2, and Sir2 gene expression was examined by reverse transcription-polymerase chain reaction (RT-PCR), and was found to be significantly increased. …
NAID 10028272350

Colocalization of 14-3-3 Proteins with SOD1 in Lewy Body-Like Hyaline Inclusions in Familial Amyotrophic Lateral Sclerosis Cases and the Animal Model.

Okamoto Yoko,Shirakashi Yoshitomo,Ihara Masafumi,Urushitani Makoto,Oono Miki,Kawamoto Yasuhiro,Yamashita Hirofumi,Shimohama Shun,Kato Shinsuke,Hirano Asao,Tomimoto Hidekazu,Ito Hidefumi,Takahashi Ryosuke
PloS one 6(5), 2011-05
… Cu/Zn superoxide dismutase (SOD1) is a major component of Lewy body-like hyaline inclusion (LBHI) found in the postmortem tissue of SOD1-linked familial amyotrophic lateral sclerosis (FALS) patients. … To further investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical analysis of 14-3-3 proteins and compared their distributions with those of SOD1 in FALS patients and SOD1-overexpressing mice. …
NAID 120003163709

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リンク元	「superoxide dismutase 1」
関連記事	「SOD」

「superoxide dismutase 1」

Superoxide dismutase 1, soluble
	; PDB rendering based on 1azv.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1AZV, 1BA9, 1DSW, 1FUN, 1HL4, 1HL5, 1KMG, 1L3N, 1MFM, 1N18, 1N19, 1OEZ, 1OZT, 1OZU, 1P1V, 1PTZ, 1PU0, 1RK7, 1SOS, 1SPD, 1UXL, 1UXM, 2AF2, 2C9S, 2C9U, 2C9V, 2GBT, 2GBU, 2GBV, 2LU5, 2NNX, 2R27, 2V0A, 2VR6, 2VR7, 2VR8, 2WKO, 2WYT, 2WYZ, 2WZ0, 2WZ5, 2WZ6, 2XJK, 2XJL, 2ZKW, 2ZKX, 2ZKY, 3CQP, 3CQQ, 3ECU, 3ECV, 3ECW, 3GQF, 3GTV, 3GZO, 3GZP, 3GZQ, 3H2P, 3H2Q, 3HFF, 3K91, 3KH3, 3KH4, 3LTV, 3QQD, 3RE0, 3T5W, 4A7G, 4A7Q, 4A7S, 4A7T, 4A7U, 4A7V, 4B3E, 4BCY, 4BCZ, 4BD4
Identifiers
Symbols	SOD1; ALS; ALS1; IPOA; SOD; hSod1; homodimer
External IDs	OMIM: 147450 MGI: 98351 HomoloGene: 392 ChEMBL: 2354 GeneCards: SOD1 Gene
EC number	1.15.1.1
Gene Ontology
Molecular function	• superoxide dismutase activity; • copper ion binding; • protein binding; • zinc ion binding; • protein phosphatase 2B binding; • protein homodimerization activity; • chaperone binding;
Cellular component	• extracellular region; • extracellular space; • nucleus; • nucleolus; • cytoplasm; • mitochondrion; • mitochondrial matrix; • peroxisome; • cytosol; • plasma membrane; • extracellular matrix; • cytoplasmic vesicle; • dendrite cytoplasm; • neuronal cell body; • protein complex;
Biological process	• activation of MAPK activity; • response to superoxide; • ovarian follicle development; • positive regulation of cytokine production; • placenta development; • retina homeostasis; • response to amphetamine; • myeloid cell homeostasis; • platelet degranulation; • double-strand break repair; • apoptotic DNA fragmentation; • glutathione metabolic process; • superoxide metabolic process; • cellular iron ion homeostasis; • spermatogenesis; • embryo implantation; • cell aging; • blood coagulation; • sensory perception of sound; • locomotory behavior; • anterograde axon cargo transport; • retrograde axon cargo transport; • regulation of blood pressure; • response to heat; • response to organic substance; • transmission of nerve impulse; • removal of superoxide radicals; • platelet activation; • response to nutrient levels; • peripheral nervous system myelin maintenance; • regulation of T cell differentiation in thymus; • regulation of multicellular organism growth; • response to drug; • response to hydrogen peroxide; • superoxide anion generation; • positive regulation of apoptotic process; • positive regulation of catalytic activity; • negative regulation of neuron apoptotic process; • response to ethanol; • negative regulation of cholesterol biosynthetic process; • regulation of protein kinase activity; • regulation of organ growth; • response to copper ion; • muscle cell homeostasis; • thymus development; • response to axon injury; • hydrogen peroxide biosynthetic process; • regulation of mitochondrial membrane potential; • heart contraction; • neurofilament cytoskeleton organization; • relaxation of vascular smooth muscle; • auditory receptor cell stereocilium organization;
	Sources: Amigo / QuickGO
RNA expression pattern
	More reference expression data
Orthologs
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