Martins Jr, Dorival and English, Ann M. 
ORCID: https://orcid.org/0000-0002-3696-7710
(2014)
SOD1 oxidation and formation of soluble aggregates in yeast: Relevance to sporadic ALS development.
Redox Biology, 2
.
pp. 632-639.
ISSN 2213-2317
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Official URL: https://doi.org/10.1016/j.redox.2014.03.005
Abstract
Misfolding and aggregation of copper–zinc superoxide dismutase (Sod1) are observed in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Mutations in Sod1 lead to familial ALS (FALS), which is a late-onset disease. Since oxidative damage to proteins increases with age, it had been proposed that oxidation of Sod1 mutants may trigger their misfolding and aggregation in FALS. However, over 90% of ALS cases are sporadic (SALS) with no obvious genetic component. We hypothesized that oxidation could also trigger the misfolding and aggregation of wild-type Sod1 and sought to confirm this in a cellular environment. Using quiescent, stationary-phase yeast cells as a model for non-dividing motor neurons, we probed for post-translational modification (PTM) and aggregation of wild-type Sod1 extracted from these cells. By size- exclusion chromatography (SEC), we isolated two populations of Sod1 from yeast: a low-molecular weight (LMW) fraction that is catalytically active and a catalytically inactive, high-molecular weight (HMW) fraction. High-resolution mass spectrometric analysis revealed that LMW Sod1 displays no PTMs but HMW Sod1 is oxidized at Cys146 and His71, two critical residues for the stability and folding of the enzyme. HMW Sod1 is also oxidized at His120, a copper ligand, which will promote loss of this catalytic metal cofactor essential for SOD activity. Monitoring the fluorescence of a Sod1-green-fluorescent-protein fusion (Sod1-GFP) extracted from yeast chromosomally expressing this fusion, we find that HMW Sod1-GFP levels increase up to 40-fold in old cells. Thus, we speculate that increased misfolding and inclusion into soluble aggregates is a consequence of elevated oxidative modifications of wild-type Sod1 as cells age. Our observations argue that oxidative damage to wild-type Sod1 initiates the protein misfolding mechanisms that give rise to SALS.
| Divisions: | Concordia University > Faculty of Arts and Science > Chemistry and Biochemistry |
|---|---|
| Item Type: | Article |
| Refereed: | Yes |
| Authors: | Martins Jr, Dorival and English, Ann M. |
| Journal or Publication: | Redox Biology |
| Date: | 2014 |
| Digital Object Identifier (DOI): | 10.106/j.redox.2014.03.005 |
| Keywords: | Wild-type Sod1 Oxidative PTMs Soluble aggregates Sporadic ALS Yeast |
| ID Code: | 985137 |
| Deposited By: | MIA MASSICOTTE |
| Deposited On: | 28 May 2019 15:17 |
| Last Modified: | 29 May 2019 12:45 |
| Additional Information: | "Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.redox.2014.03.005" |
References:
[1] H. Kawamata, G. Manfredi, Import, maturation, and function of SOD1 and its copper chaperone CCS in the mitochondrial intermembrane space, Antioxidants & Redox Signaling 13 (2010) 1375–1384. http://dx.doi.org/10.1089/ars.2010.3212 , 20367259 .[2] L.A. Sturtz, K. Diekert, L.T. Jensen, R. Lill, V.C. Culotta, A fraction of yeast Cu, Zn-superoxide dismutase and its metallochaperone, CCS, localize to the intermembrane space of mitochondria. A physiological role for SOD1 in guarding against mitochondrial oxidative damage, Journal of Biological Chemistry 276 (2001) 38084–38089, http://doi.org/10.1074/jbc.M105296200 , 11500508 .
[3] V.D. Longo, E.B. Gralla, J.S. Valentine, Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae . Mitochondrial production of toxic oxygen species in vivo, Journal of Biological Chemistry 271 (1996) 12275–12280. http://dx.doi.org/10.1074/jbc.271.21.12275 , 8647826 .
[4] V.K. Mulligan, A. Chakrabartty, Protein misfolding in the late-onset neurodegenerative diseases: common themes and the unique case of amyotrophic lateral sclerosis, Proteins 81 (2013) 1285–1303. http://dx.doi.org/10.1002/prot.24285 , 23508986 .
[5] J. Choi, H.D. Rees, S.T. Weintraub, A.I. Levey, L.S. Chin, L. Li, Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases, Journal of Biological Chemistry 280 (2005) 11648–11655. http://dx.doi.org/10.1074/jbc.M414327200 , 15659387 .
[6] O. Abel, J.F. Powell, P.M. Andersen, A. Al-Chalabi, ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics, Human Mutation 33 (2012) 1345–1351. http://dx.doi.org/10.1002/humu.22157 , 22753137 .
[7] J.S. Valentine, P.J. Hart, Misfolded CuZnSOD and amyotrophic lateral sclerosis, Proceedings of the National Academy of Sciences of the United States of America 100 (2003) 3617–3622. http://dx.doi.org/10.1073/pnas.0730423100 , 12655070 .
[8] J.S. Valentine, P.A. Doucette, S.Z. Potter, Copper–zinc superoxide dismutase and amyotrophic lateral sclerosis, Annual Review of Biochemistry 74 (2005) 563–593. http://dx.doi.org/10.1146/annurev.biochem.72.121801.161647 , 15952898 .
[9] A. Stieber, J.O. Gonatas, N.K. Gonatas, Aggregates of mutant protein appear progressively in dendrites, in periaxonal processes of oligodendrocytes, and in neuronal and astrocytic perikarya of mice expressing the SOD1(G93A) mutation of familial amyotrophic lateral sclerosis, Journal of the Neurological Sciences 177 (2000) 114–123. http://doi.org/10.1016/S0022-510X(00)00351-8 , 10980307 .
[10] L.I. Grad, W.C. Guest, A. Yanai, E. Pokrishevsky, M.A. O'Neill, E. Gibbs, et al, Intermolecular transmission of superoxide dismutase 1 misfolding in living cells, Proceedings of the National Academy of Sciences of the United States of America 108 (2011) 16398–16403. http://dx.doi.org/10.1073/pnas.1102645108 , 21930926 .
[11] R. Rakhit, P. Cunningham, A. Furtos-Matei, S. Dahan, X.F. Qi, J.P. Crow, et al, Oxidation-induced misfolding and aggregation of superoxide dismutase and its implications for amyotrophic lateral sclerosis, Journal of Biological Chem- istry 277 (2002) 47551–47556. http://dx.doi.org/10.1074/jbc.M207356200 , 12356748 .
[12] R. Rakhit, J.P. Crow, J.R. Lepock, L.H. Kondejewski, N.R. Cashman, A. Chakrabartty, Monomeric Cu,Zn-superoxide dismutase is a common misfolding intermediate in the oxidation models of sporadic and familial amyotrophic lateral sclerosis, Journal of Biological Chemistry 279 (2004) 15499–15504. http://doi.org/10.1074/jbc.M313295200 , 14734542 .
13] A. Kerman, H. Liu, S. Croul, J. Bilbao, E. Rogaeva, L. Zinman, et al, Amyotrophic lateral sclerosis is a non-amyloid disease in which extensive misfolding of SOD1 is unique to the familial form, Acta Neuropathologica 119 (2010) 335–344. http://doi.org/10.1007/s00401-010-0646-5 , 20111867 .
[14] N. Brandes, H. Tienson, A. Lindemann, V. Vitvitsky, D. Reichmann, R. Banerjee, et al, Time line of redox events in aging postmitotic cells, ELife 2 (2013) e00306, 23390587 .
[15] B.S. Berlett, E.R. Stadtman, Protein oxidation in aging, disease, and oxidative stress, Journal of Biological Chemistry 272 (1997) 20313–20316. http://doi.org/10.1074/jbc.272.33.20313 , 9252331 .
[16] K. Uchida, S. Kawakishi, Identification of oxidized histidine generated at the active site of Cu,Zn-superoxide dismutase exposed to H 2 O 2 . Selective generation of 2-oxo-histidine at the histidine 118, Journal of Biological Chemistry 269 (1994) 2405–2410, 8300566 .
[17] R.H. Gottfredsen, U.G. Larsen, J.J. Enghild, S.V. Petersen, Hydrogen peroxide in- duce modifications of human extracellular superoxide dismutase that results in enzyme inhibition, Redox Biology 1 (2013) 24–31. http://dx.doi.org/10.1016/j.redox.2012.12.004 , 24024135 .
[18] D.C. Ramirez, S.E.G. Mejiba, R.P. Mason, Mechanism of hydrogen peroxide- induced Cu,Zn-superoxide dismutase-centered radical formation as explored by immuno-spin trapping: the role of copper- and carbonate radical anion-mediated oxidations, Free Radical Biology & Medicine 38 (2005) 201–214. http://dx.doi.org/10.1016/j.freeradbiomed.2004.10.008 , 15607903 .
[19] K. Ranguelova, D. Ganini, M.G. Bonini, R.E. London, R.P. Mason, Kinetics of the oxidation of reduced Cu,Zn-superoxide dismutase by peroxymonocarbonate, Free Radical Biology & Medicine 53 (2012) 589–594. http://doi.org/10.1016/j.freeradbiomed.2012.04.029 , 22569304 .
[20] B.R. Roberts, J.A. Tainer, E.D. Getzoff, D.A. Malencik, S.R. Anderson, V.C. Bomben, et al, Structural characterization of zinc-deficient human superoxide dismutase and implications for ALS, Journal of Molecular Biology 373 (2007) 877–890. http://dx.doi.org/10.1016/j.jmb.2007.07.043 , 17888947 .
[21] T. Kurahashi, A. Miyazaki, S. Suwan, M. Isobe, Extensive investigations on oxidized amino acid residues in H 2 O 2 -treated Cu,Zn-SOD protein with LC-ESI–Q- TOF-MS, MS / MS for the determination of the copper-binding site, Journal of the American Chemical Society 123 (2001) 9268–9278. http://doi.org/10.1021/ja015953r , 11562208 .
[22] S.C. Barber, P.J. Shaw, Oxidative stress in ALS: key role in motor neuron injury and therapeutic target, Free Radical Biology & Medicine 48 (2010) 629–641. http://dx.doi.org/10.1016/j.freeradbiomed.2009.11.018 , 19969067 .
[23] E. Linares, L.V. Seixas, J.N. dos Prazeres, F.V.L. Ladd, A.A.B.L. Ladd, A.A. Coppi, et al, Tempol moderately extends survival in a hSOD1(G93A) ALS rat model by inhibiting neuronal cell loss, oxidative damage and levels of non-native hSOD1(G93A) forms, PloS One 8 (2013) e55868. http://doi.org/10.1371/journal.pone.0055868 , 23405225 .
[24] E. Ghezzo-Schoneich, S.W. Esch, V.S. Sharov, C. Schoneich, Biological aging does not lead to the accumulation of oxidized Cu,Zn-superoxide dismutase in the liver of F344 rats, Free Radical Biology & Medicine 30 (2001) 858–864. http://doi.org/10.1016/S0891-5849(01)00473-7 , 11295528 .
[25] M.H. Barros, F.M.d. Cunha, G.A. Oliveira, E.B. Tahara, A.J. Kowaltowski, Yeast as a model to study mitochondrial mechanisms in ageing, Mechanisms of Ageing and Development 131 (2010) 494–502. http://dx.doi.org/10.1016/j.mad.2010.04.008 , 20450928 .
[26] P.W. Piper, Long-lived yeast as a model for ageing research, Yeast (Chichester, England) 23 (2006) 215–226. http://dx.doi.org/10.1002/yea.1354 , 16498698 .
[27] V.D. Longo, G.S. Shadel, M. Kaeberlein, B. Kennedy, Replicative and chronological aging in Saccharomyces cerevisiae , Cell Metabolism 16 (2012) 18–31. http://doi.org/10.1016/j.cmet.2012.06.002 , 22768836 .
[28] P. Fabrizio, V.D. Longo, The chronological life span of Saccharomyces cerevisiae , Aging Cell 2 (2003) 73–81. http://dx.doi.org/10.1046/j.1474-9728.2003.00033.x , 12882320 .
[29] V. Khurana, S. Lindquist, Modelling neurodegeneration in Saccharomyces cerevisiae : why cook with Baker ’ s yeast? Nature Reviews. Neuroscience 11 (2010) 436–449. http://dx.doi.org/10.1038/nrn2809 , 20424620 .
[30] H. Jiang, A.M. English, Phenotypic analysis of the ccp1Delta and ccp1Delta- ccp1W191F mutant strains of Saccharomyces cerevisiae indicates that cytochrome c peroxidase functions in oxidative-stress signaling, Journal of Inorganic Biochemistry 100 (2006) 1996–2008. http://dx.doi.org/10.1016/j.jinorgbio.2006.07.017 , 17011626 .
[31] M.M. Bradford, A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding, Analytical Biochemistry 72 (1976) 248–254. http://doi.org/10.1016/0003-2697(76)90527-3 , 942051 .
[32] C.J. Weydert, J.J. Cullen, Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue, Nature Protocols 5 (2010) 51–66. http://dx.doi.org/10.1038/nprot.2009.197 , 20057381 .
[33] A. Tiwari, L.J. Hayward, Familial amyotrophic lateral sclerosis mutants of copper / zinc superoxide dismutase are susceptible to disulfide reduction, Journal of Biological Chemistry 278 (2003) 5984–5992. https://doi.org/10.1074/jbc.M210419200 , 12458194 .
[34] M.J. Lindberg, J. Normark, A. Holmgren, M. Oliveberg, Folding of human superoxide dismutase: disulfide reduction prevents dimerization and produces marginally stable monomers, Proceedings of the National Academy of Sciences of the United States of America 101 (2004) 15893–15898. http://dx.doi.org/10.1073/pnas.0403979101 , 15522970 .
[35] S. Ghosh, B. Willard, S.A. Comhair, P. Dibello, W. Xu, S. Shiva, et al, Disulfide bond as a switch for copper–zinc superoxide dismutase activity in asthma, Antioxidants & Redox Signaling 18 (2013) 412–423, 22867017 .
[36] S.M. Lynch, S.A. Boswell, W. Colon, Kinetic stability of Cu / Zn superoxide dismutase is dependent on its metal ligands: implications for ALS, Biochemistry 43 (2004) 16525–16531. http://dx.doi.org/10.1021/bi048831v , 15610047 .
[37] M. Synofzik, D. Ronchi, I. Keskin, A.N. Basak, C. Wilhelm, C. Gobbi, et al, Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS, Human Molecular Genetics 21 (2012) 3568–3574. http://dx.doi.org/10.1093/hmg/dds188 .
[38] C.M.J. Higgins, C.W. Jung, Z.S. Xu, ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes, BMC Neuroscience 4 (2003) 16. http://doi.org/10.1186/1471-2202-4-16 , 12864925 .
[39] E.L. Bastow, C.W. Gourlay, M.F. Tuite, Using yeast models to probe the molecular basis of amyotrophic lateral sclerosis, Biochemical Society Transactions 39 (2011) 1482–1487. http://dx.doi.org/10.1042/BST0391482 , 21936838 .
[40] D.F. Tardiff, N.T. Jui, V. Khurana, M.A. Tambe, M.L. Thompson, C.Y. Chung, et al, Yeast reveal a “druggable” Rsp5 / Nedd4 network that ameliorates alpha-synuclein toxicity in neurons, Science (New York, NY) 342 (2013) 979–983. http://dx.doi.org/10.1126/science.1245321 , 24158909 .
[41] D. Martins, M. Kathiresan, A.M. English, Cytochrome c peroxidase is a mitochondrial heme-based H 2 O 2 sensor that modulates antioxidant defense, Free Radical Biology & Medicine 65 (2013) 541–551. http://doi.org/10.1016/j.freeradbiomed.2013.06.037
[42] D. Martins, V.I. Titorenko, A.M. English, Cells with impaired mitochondrial H 2 O 2 sensing generate less •OH radicals and live longer, Antioxidants and Redox Signaling (2014). http://dx.doi.org/10.1089/ars.2013.5575 , in press.
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