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Essentiality of selenium for brain development


The trace element selenium (Se) was discovered by the Swedish scientist Jöns Jacob Berzelius in 1817. Its essentiality was discovered in 1957 by Schwarz and Foltz. In biological systems, Se exerts its essential role as the 21st amino acid, selenocysteine (Sec). Because Sec differs from cysteine (Cys) only by the replacement of sulfur for Se and because Cys incorporation presents a canonical translational insertion, the actual biological advantage of selenolate-based over thiolate-based catalysis has remained elusive. Anyhow, as part of the gluthadione peroxidase, selenium is known as an antioxidant that protects several cell types in mammals, fish, birds, nematodes and bacteria from oxidative breakdown.

The new study:
While the essentiality of selenium for humans, many animals and some bacteria is well known since about 60 years, the research team around Marcus Conrad (team leader at the Institute for Developmental Genetics, IDG at the Helmholtz Zentrum München) together with Carsten Berndt (Molekulare Neurologie  - Universitätsklinikum Düsseldorf) and Gereon Poschmann (Molecular Proteomics Laboratory, Heinrich-Heine Universität) were able to show why.    

In  the framework of the DFG funded program „Dynamics of Thiol-based Redox Switches in Cellular Physiology“ the researchers are investigating the role of oxidoreductases for the development of neurons and especially the cell death induced by the presence of iron (ferroptose).  In order to study the role of the enzyme glutathion peroxidase 4 (GPX4), one of the 25 selenoproteins in humans, the researchers developed a mouse model with modified GPX4. 
Reaction pathway showing the critical role of GPX-4 against ferroptosis due to oxidative stress
The GPX4-Cys variant is highly susceptible to hydroperoxide-induced inactivation - Hydroperoxide induces ferroptosis in Gpx4cys/cys cells - Selenium-containing GPX4 is necessary for full viability of mice

They observed that animals with modified GPX4, having incorporated sulfur instead of selenium, were not living for more than 3 weeks. Searching for the reason of death, they found certain neuron types were missing which were broken down during brain development induced by ferroptosis.

The original publication:

Irina Ingold, Carsten Berndt, Sabine Schmitt, Sebastian Doll, Gereon Poschmann, Katalin Buday, Antonella Roveri, Xiaoxiao Peng, Florencio Porto Freitas, Tobias Seibt, Lisa Mehr, Michaela Aichler, Axel Walch, Daniel Lamp, Martin Jastroch, Sayuri Miyamoto, Wolfgang Wurst, Fulvio Ursini, Elias S.J. Arnér, Noelia Fradejas-Villar, Ulrich Schweizer, Hans Zischka, José Pedro Friedmann Angeli, Marcus Conrad, Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis, Cell, 2018. doi: 10.1016/j.cell.2017.11.048

Related publications:

W.S. Hambright, R.S. Fonseca, L.  Chen, R. Na, Q. Ran, Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration. Redox Biol., 12 (2017) 8–17. DOI: 10.1016/j.redox.2017.01.021

H.J. Reich, R.J. Hondal, Why Nature chose selenium. ACS Chem. Biol., 11/4 (2016) 821–841. DOI: 10.1021/acschembio.6b00031
S.H. Brütsch, C.C. Wang, L. Li, H. Stender, N. Neziroglu, C. Richter, H. Kuhn, A. Borchert, Expression of inactive glutathione peroxidase 4 leads to embryonic lethality, and inactivation of the Alox15 gene does not rescue such knock-in mice. Antioxid. Redox. Signal. 22 (2015) 281–293. DOI: 10.1089/ars.2014.5967

I. Ingold, M. Aichler, E. Yefremova, A. Roveri, K. Buday, S. Doll, A. Tasdemir, N. Hoffard, W. Wurst, A. Walch, Expression of a catalytically inactive mutant form of glutathione peroxidase 4 (Gpx4) confers a dominantnegative effect in male fertility. J. Biol. Chem., 290 (2015) 14668–14678. DOI: 10.1074/jbc.M115.656363

J.P. Friedmann Angeli, M. Schneider, B. Proneth, Y.Y. Tyurina, V.A. Tyurin, V.J. Hammond, N. Herbach, M. Aichler, A. Walch, E. Eggenhofer, Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat. Cell Biol., 16 (2014) 1180–1191. DOI: 10.1038/ncb3064

X. Peng, P.K. Mandal, V.P. Kaminskyy, A. Lindqvist, M. Conrad, E.S. Arnér, Sec-containing TrxR1 is essential for self-sufficiency of cells by control of glucose-derived H2O2. Cell Death Dis., 5 (2014) e1235. DOI: 10.1038/cddis.2014.209

D.L. Hatfield, P.A. Tsuji, B.A. Carlson, V.N. Gladyshev, Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem. Sci., 39 (2014) 112–120. DOI: 10.1016/j.tibs.2013.12.007

E.K. Wirth, B.S. Bharathi, D. Hatfield, M. Conrad, M. Brielmeier, U. Schweizer, Cerebellar hypoplasia in mice lacking selenoprotein biosynthesis in neurons. Biol. Trace Elem. Res., 158 (2014) 203–210. DOI: 10.1007/s12011-014-9920-z

G.W. Snider, E. Ruggles, N. Khan, R.J. Hondal, Selenocysteine confers resistance to inactivation by oxidation in thioredoxin reductase: comparison of selenium and sulfur enzymes. Biochemistry, 52 (2013) 5472–5481. DOI: 10.1021/bi400462j

E.K. Wirth, M. Conrad, J. Winterer, C. Wozny, B.A. Carlson, S. Roth, D. Schmitz, G.W. Bornkamm, V. Coppola, L. Tessarollo, Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. FASEB J., 24 (2010) 844–852. DOI: 10.1096/fj.09-143974

N.E. Savaskan, A.U. Bräuer, M. Kühbacher, I.Y. Eyüpoglu, A. Kyriakopoulos, O. Ninnemann, D. Behne, R. Nitsch, Selenium deficiency increases susceptibility to glutamate-induced excitotoxicity. FASEB J., 17 (2003) 112–114. DOI: 10.1096/fj.02-0067fje

L.J. Yant, Q. Ran, L. Rao, H. Van Remmen, T. Shibatani, J.G. Belter, L. Motta, A. Richardson, T.A. Prolla, The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic. Biol. Med., 34 (2003) 496–502. DOI: 10.1016/S0891-5849(02)01360-6

M.R. Bösl, K. Takaku, M. Oshima, S. Nishimura, M.M. Taketo, Early embryonic lethality caused by targeted disruption of the mouse selenocysteine tRNA gene (Trsp), Proc. Natl. Acad. Sci. USA, 94 (1997) 5531–5534. DOI: 10.1073/pnas.94.11.5531

V.T. Ramaekers, M. Calomme, D. Vanden Berghe, W. Makropoulos, Selenium deficiency triggering intractable seizures. Neuropediatrics, 25 (1994) 217–223.     DOI: 10.1055/s-2008-1073025

K. Schwarz, C.M. Foltz, Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration, J. Am. Chem. Soc., 79 (1957) 3292-3293. DOI: 10.1021/ja01569a087

Related EVISA Resources

Link database: All about proteins containing selenium
Link database: Selenium and human health

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last time modified: February, 14, 2018


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