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== Interactions ==
== Interactions ==


SOD1 has been shown to [[Protein-protein interaction|interact]] with [[CCS (gene)|CCS]]<ref name="pmid9726962">{{cite journal | author = Casareno RL, Waggoner D, Gitlin JD | title = The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase | journal = J. Biol. Chem. | volume = 273 | issue = 37 | pages = 23625–8 | year = 1998 | month = September | pmid = 9726962 | doi = 10.1074/jbc.273.37.23625| url = | issn = }}</ref> and [[Bcl-2]].<ref name="pmid15233914">{{cite journal | author = Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH | title = Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria | journal = Neuron | volume = 43 | issue = 1 | pages = 19–30 | year = 2004 | month = July | pmid = 15233914 | doi = 10.1016/j.neuron.2004.06.021 | url = | issn = }}</ref> <ref name="pmid20561900">{{cite journal | author = Cova E, Ghiroldi A, Guareschi S, Mazzini G, Gagliardi S, Davin A, Bianchi M, Ceroni M, Cereda C | title = G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis | journal = Cell Signal | volume = 22 | issue = 10 | pages = 1477–1484 | year = 2010 | month = October | pmid = 20561900 | doi = 10.1016/j.cellsig.2010.05.016 | url = | issn = }}</ref>
SOD1 has been shown to [[Protein-protein interaction|interact]] with [[CCS (gene)|CCS]]<ref name="pmid9726962">{{cite journal | author = Casareno RL, Waggoner D, Gitlin JD | title = The copper chaperone CCS directly interacts with copper/zinc superoxide dismutase | journal = J. Biol. Chem. | volume = 273 | issue = 37 | pages = 23625–8 | year = 1998 | month = September | pmid = 9726962 | doi = 10.1074/jbc.273.37.23625| url = | issn = }}</ref> and [[Bcl-2]].<ref name="pmid15233914">{{cite journal | author = Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH | title = Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria | journal = Neuron | volume = 43 | issue = 1 | pages = 19–30 | year = 2004 | month = July | pmid = 15233914 | doi = 10.1016/j.neuron.2004.06.021 | url = | issn = }}</ref> <ref name="pmid20561900">{{cite journal | author = Cova E, Ghiroldi A, Guareschi S, Mazzini G, Gagliardi S, Davin A, Bianchi M, Ceroni M, Cereda C | title = G93A SOD1 alters cell cycle in a cellular model of Amyotrophic Lateral Sclerosis | journal = Cell Signal | volume = 22 | issue = 10 | pages = 1477–1484 | year = 2010 | month = October | pmid = 20561900 | doi = 10.1016/j.cellsig.2010.05.016 | url = | issn = }}</ref> <ref name="pmid17122939">{{cite journal | author = Cereda C, Cova E, Di Poto C, Galli A, Mazzini G, Corato M, Ceroni M | title = Effect of nitric oxide on lymphocytes from sporadic amyotrophic lateral sclerosis patients: toxic or protective role? | journal = Neurological Sciences | volume = 27 | issue = 5| pages = 312-316 | year = 2006 | month = November | pmid = 17122939 | doi = 10.1007/s10072-006-0702-z| url = | issn = }}</ref>


==References==
==References==

Revision as of 20:00, 25 January 2012

Template:PBB Superoxide dismutase [Cu-Zn] also known as superoxide dismutase 1 or SOD1 is an enzyme that in humans is encoded by the SOD1 gene. SOD1 is one of three human superoxide dismutases. [1] [2]

Function

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

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)

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

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

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 typically 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

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

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

References

  1. ^ Milani P, Gagliardi S, Cova E, Cereda C (2011). "SOD1 Transcriptional and Posttranscriptional Regulation and Its Potential Implications in ALS". Neurol Res Int. doi:10.1155/2011/458427. PMC 3096450. PMID 21603028.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  2. ^ Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, Donaldson D, Goto J, O'Regan JP, Deng HX (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  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 (2006). "SOD1: a candidate gene for keratoconus". Invest. Ophthalmol. Vis. Sci. 47 (8): 3345–51. doi:10.1167/iovs.05-1500. PMID 16877401. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ Muller FL, Lustgarten MS, Jang Y, Richardson A, Van Remmen H (2007). "Trends in oxidative aging theories". Free Radic. Biol. Med. 43 (4): 477–503. doi:10.1016/j.freeradbiomed.2007.03.034. PMID 17640558. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Conwit RA (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  7. ^ Al-Chalabi A, Leigh PN (2000). "Recent advances in amyotrophic lateral sclerosis". Curr. Opin. Neurol. 13 (4): 397–405. doi:10.1097/00019052-200008000-00006. PMID 10970056. {{cite journal}}: Unknown parameter |month= ignored (help)
  8. ^ Gagliardi S, Cova E, Davin A, Guareschi S, Abel K, Alvisi E, Laforenza U, Ghidoni R, Cashman JR, Ceroni M, Cereda C (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Rosen DR, Bowling AC, Patterson D, Usdin TB, Sapp P, Mezey E, McKenna-Yasek D, O'Regan J, Rahmani Z, Ferrante RJ (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  10. ^ Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, Schoenfeld DA, Hosler BA, Horvitz HR, Brown RH (1997). "Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis". Ann. Neurol. 41 (2): 210–21. doi:10.1002/ana.410410212. PMID 9029070. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  11. ^ a b Valentine JS, Hart PJ (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. {{cite journal}}: Unknown parameter |month= ignored (help)
  12. ^ Broom WJ, Johnson DV, Auwarter KE, Iafrate AJ, Russ C, Al-Chalabi A, Sapp PC, McKenna-Yasek D, Andersen PM, Brown RH (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b c Muller FL, Liu Y, Jernigan A, Borchelt D, Richardson A, Van Remmen H (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Bergemalm D, Jonsson PA, Graffmo KS, Andersen PM, Brännström T, Rehnmark A, Marklund SL (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  15. ^ Casareno RL, Waggoner D, Gitlin JD (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  16. ^ Pasinelli P, Belford ME, Lennon N, Bacskai BJ, Hyman BT, Trotti D, Brown RH (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  17. ^ Cova E, Ghiroldi A, Guareschi S, Mazzini G, Gagliardi S, Davin A, Bianchi M, Ceroni M, Cereda C (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Cereda C, Cova E, Di Poto C, Galli A, Mazzini G, Corato M, Ceroni M (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Further reading

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