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Superoxide dismutase 1, soluble
Protein SOD1 PDB 1azv.png
PDB rendering based on 1azv.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols SOD1 ; ALS; ALS1; HEL-S-44; IPOA; SOD; hSod1; homodimer
External IDs OMIM147450 MGI98351 HomoloGene392 ChEMBL: 2354 GeneCards: SOD1 Gene
EC number
RNA expression pattern
PBB GE SOD1 200642 at tn.png
More reference expression data
Species Human Mouse
Entrez 6647 20655
Ensembl ENSG00000142168 ENSMUSG00000022982
UniProt P00441 P08228
RefSeq (mRNA) NM_000454 NM_011434
RefSeq (protein) NP_000445 NP_035564
Location (UCSC) Chr 21:
33.03 – 33.04 Mb
Chr 16:
90.22 – 90.23 Mb
PubMed search [1] [2]

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]


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). In Iceland only SOD1-G93S has been found. 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 about 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 Laboratory, 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 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] Further studies have shown that the pathogenesis of the G93A and H46R models are clearly distinct; some drugs and genetic interventions that are highly beneficial/detrimental in one model have either the opposite or no effect in the other.[15][15][16][17]


SOD1 has been shown to interact with CCS[18] and Bcl-2.[19][20][21][22]


  1. ^ 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. 
  2. ^ 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. 
  3. ^ a b "Entrez Gene: SOD1 superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))". 
  4. ^ 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. 
  5. ^ 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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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. 
  14. ^ 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. 
  15. ^ a b Pan L, Yoshii Y, Otomo A, Ogawa H, Iwasaki Y, Shang HF, Hadano S (2012). "Different human copper-zinc superoxide dismutase mutants, SOD1G93A and SOD1H46R, exert distinct harmful effects on gross phenotype in mice". PLoS ONE 7 (3): e33409. doi:10.1371/journal.pone.0033409. PMC 3306410. PMID 22438926. 
  16. ^ Bhattacharya A, Bokov A, Muller FL, Jernigan AL, Maslin K, Diaz V, Richardson A, Van Remmen H (2012). "Dietary restriction but not rapamycin extends disease onset and survival of the H46R/H48Q mouse model of ALS". Neurobiol. Aging 33 (8): 1829–32. doi:10.1016/j.neurobiolaging.2011.06.002. PMID 21763036. 
  17. ^ Vargas MR, Johnson DA, Johnson JA (2011). "Decreased glutathione accelerates neurological deficit and mitochondrial pathology in familial ALS-linked hSOD1(G93A) mice model". Neurobiol. Dis. 43 (3): 543–51. doi:10.1016/j.nbd.2011.04.025. PMC 3139005. PMID 21600285. 
  18. ^ 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. 
  19. ^ 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. 
  20. ^ 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. 
  21. ^ 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. 
  22. ^ Cova E, Cereda C, Galli A, Curti D, Finotti C, Di Poto C, Corato M, Mazzini G, Ceroni M (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. 

Further reading[edit]

  • de Belleroche J, Orrell R, King A (1996). "Familial amyotrophic lateral sclerosis/motor neurone disease (FALS): a review of current developments.". J. Med. Genet. 32 (11): 841–7. doi:10.1136/jmg.32.11.841. PMC 1051731. PMID 8592323. 
  • Ceroni M, Curti D, Alimonti D (2002). "Amyotrophic lateral sclerosis and SOD1 gene: an overview.". Funct. Neurol. 16 (4 Suppl): 171–80. PMID 11996514. 
  • Zelko IN, Mariani TJ, Folz RJ (2003). "Superoxide dismutase multigene family: a comparison of the CuZn-SOD (SOD1), Mn-SOD (SOD2), and EC-SOD (SOD3) gene structures, evolution, and expression.". Free Radic. Biol. Med. 33 (3): 337–49. doi:10.1016/S0891-5849(02)00905-X. PMID 12126755. 
  • Hadano S (2002). "[Causative genes for familial amyotrophic lateral sclerosis]". Seikagaku 74 (6): 483–9. PMID 12138710. 
  • Noor R, Mittal S, Iqbal J (2003). "Superoxide dismutase--applications and relevance to human diseases.". Med. Sci. Monit. 8 (9): RA210–5. PMID 12218958. 
  • Potter SZ, Valentine JS (2004). "The perplexing role of copper-zinc superoxide dismutase in amyotrophic lateral sclerosis (Lou Gehrig's disease).". J. Biol. Inorg. Chem. 8 (4): 373–80. doi:10.1007/s00775-003-0447-6. PMID 12644909. 
  • Rotilio G, Aquilano K, Ciriolo MR (2004). "Interplay of Cu,Zn superoxide dismutase and nitric oxide synthase in neurodegenerative processes.". IUBMB Life 55 (10-11): 629–34. doi:10.1080/15216540310001628717. PMID 14711010. 
  • Jafari-Schluep HF, Khoris J, Mayeux-Portas V, Hand C, Rouleau G, Camu W (2004). "[Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature]". Rev. Neurol. (Paris) 160 (1): 44–50. PMID 14978393. 
  • Faraci FM, Didion SP (2005). "Vascular protection: superoxide dismutase isoforms in the vessel wall.". Arterioscler. Thromb. Vasc. Biol. 24 (8): 1367–73. doi:10.1161/01.ATV.0000133604.20182.cf. PMID 15166009. 
  • Gagliardi S, Ogliari P, Davin A, Corato M, Cova E, Abel K, Cashman JR, Ceroni M, Cereda C (2011). "Flavin-containing monooxygenase mRNA levels are up-regulated in als brain areas in SOD1-mutant mice". Neurotoxicity Research 20 (2): 150–158. doi:10.1007/s12640-010-9230-y. PMID 21082301. 
  • Battistini S, Ricci C, Lotti EM, Benigni M, Gagliardi S, Zucco R, Bondavalli M, Marcello N, Ceroni M, Cereda C (2010). "Severe familial ALS with a novel exon 4 mutation (L106F) in the SOD1 gene". Journal of the Neurological Sciences 293 (1): 112–115. doi:10.1016/j.jns.2010.03.009. PMID 20385392. 

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