Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1 - PubMed (original) (raw)
. 2007 Sep 21;282(38):28087-95.
doi: 10.1074/jbc.M704465200. Epub 2007 Jul 31.
Affiliations
- PMID: 17666395
- DOI: 10.1074/jbc.M704465200
Free article
Disulfide bond mediates aggregation, toxicity, and ubiquitylation of familial amyotrophic lateral sclerosis-linked mutant SOD1
Jun-ichi Niwa et al. J Biol Chem. 2007.
Free article
Abstract
Mutations in the Cu/Zn-superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS) through the gain of a toxic function; however, the nature of this toxic function remains largely unknown. Ubiquitylated aggregates of mutant SOD1 proteins in affected brain lesions are pathological hallmarks of the disease and are suggested to be involved in several proposed mechanisms of motor neuron death. Recent studies suggest that mutant SOD1 readily forms an incorrect disulfide bond upon mild oxidative stress in vitro, and the insoluble SOD1 aggregates in spinal cord of ALS model mice contain multimers cross-linked via intermolecular disulfide bonds. Here we show that a non-physiological intermolecular disulfide bond between cysteines at positions 6 and 111 of mutant SOD1 is important for high molecular weight aggregate formation, ubiquitylation, and neurotoxicity, all of which were dramatically reduced when the pertinent cysteines were replaced in mutant SOD1 expressed in Neuro-2a cells. Dorfin is a ubiquityl ligase that specifically binds familial ALS-linked mutant SOD1 and ubiquitylates it, thereby promoting its degradation. We found that Dorfin ubiquitylated mutant SOD1 by recognizing the Cys(6)- and Cys(111)-disulfide cross-linked form and targeted it for proteasomal degradation.
Similar articles
- Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.
Furukawa Y, Fu R, Deng HX, Siddique T, O'Halloran TV. Furukawa Y, et al. Proc Natl Acad Sci U S A. 2006 May 2;103(18):7148-53. doi: 10.1073/pnas.0602048103. Epub 2006 Apr 24. Proc Natl Acad Sci U S A. 2006. PMID: 16636274 Free PMC article. - A limited role for disulfide cross-linking in the aggregation of mutant SOD1 linked to familial amyotrophic lateral sclerosis.
Karch CM, Borchelt DR. Karch CM, et al. J Biol Chem. 2008 May 16;283(20):13528-37. doi: 10.1074/jbc.M800564200. Epub 2008 Mar 3. J Biol Chem. 2008. PMID: 18316367 Free PMC article. - Dorfin-CHIP chimeric proteins potently ubiquitylate and degrade familial ALS-related mutant SOD1 proteins and reduce their cellular toxicity.
Ishigaki S, Niwa J, Yamada S, Takahashi M, Ito T, Sone J, Doyu M, Urano F, Sobue G. Ishigaki S, et al. Neurobiol Dis. 2007 Feb;25(2):331-41. doi: 10.1016/j.nbd.2006.09.017. Epub 2006 Dec 6. Neurobiol Dis. 2007. PMID: 17157513 - Transgenic mouse model for familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation.
Shibata N. Shibata N. Neuropathology. 2001 Mar;21(1):82-92. doi: 10.1046/j.1440-1789.2001.00361.x. Neuropathology. 2001. PMID: 11304046 Review. - Immature copper-zinc superoxide dismutase and familial amyotrophic lateral sclerosis.
Seetharaman SV, Prudencio M, Karch C, Holloway SP, Borchelt DR, Hart PJ. Seetharaman SV, et al. Exp Biol Med (Maywood). 2009 Oct;234(10):1140-54. doi: 10.3181/0903-MR-104. Epub 2009 Jul 13. Exp Biol Med (Maywood). 2009. PMID: 19596823 Free PMC article. Review.
Cited by
- Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.
Huang M, Liu YU, Yao X, Qin D, Su H. Huang M, et al. Transl Neurodegener. 2024 May 29;13(1):28. doi: 10.1186/s40035-024-00416-x. Transl Neurodegener. 2024. PMID: 38811997 Free PMC article. Review. - Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.
Dogan M, Teralı K, Eroz R, Kılıç H, Gezdirici A, Gönüllü B. Dogan M, et al. Mol Biol Rep. 2024 Apr 26;51(1):580. doi: 10.1007/s11033-024-09513-6. Mol Biol Rep. 2024. PMID: 38668754 - Oxidized SOD1 accelerates cellular senescence in neural stem cells.
Guan T, Guo Y, Zhou T, Yu Q, Sun J, Sun B, Zhang G, Kong J. Guan T, et al. Stem Cell Res Ther. 2024 Feb 27;15(1):55. doi: 10.1186/s13287-024-03669-5. Stem Cell Res Ther. 2024. PMID: 38414053 Free PMC article. - Properties of biomolecular condensates defined by Activator of G-protein Signaling 3.
Vural A, Lanier SM. Vural A, et al. J Cell Sci. 2024 Feb 15;137(4):jcs261326. doi: 10.1242/jcs.261326. Epub 2024 Feb 22. J Cell Sci. 2024. PMID: 38264908 - In Vitro Analysis of Biological Activity of Circulating Cell-Free DNA Isolated from Blood Plasma of Schizophrenic Patients and Healthy Controls-Part 2: Adaptive Response.
Kostyuk SV, Ershova ES, Martynov AV, Artyushin AV, Porokhovnik LN, Malinovskaya EM, Jestkova EM, Zakharova NV, Kostyuk GP, Izhevskaia VL, Kutsev SI, Veiko NN. Kostyuk SV, et al. Genes (Basel). 2022 Dec 4;13(12):2283. doi: 10.3390/genes13122283. Genes (Basel). 2022. PMID: 36553550 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Miscellaneous