Effect of the human SOD1‑G93A gene on the Nrf2/ARE signaling pathway in NSC‑34 cells

Wang,Fumin; Lu,Yucheng; Qi,Faying; Su,Quanping; Wang,Long; You,Cuiping; Che,Fengyuan; Yu,Jixu

doi:10.3892/mmr.2014.2087

Effect of the human SOD1‑G93A gene on the Nrf2/ARE signaling pathway in NSC‑34 cells

Authors:
- Fumin Wang
- Yucheng Lu
- Faying Qi
- Quanping Su
- Long Wang
- Cuiping You
- Fengyuan Che
- Jixu Yu
View Affiliations

Affiliations: Department of Clinical Neurology, School of Neurology, Weifang Medical University, Weifang, Shandong 261053, P.R. China, Central Laboratory, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China, Department of Neurology, Linyi People's Hospital, Linyi, Shandong 276003, P.R. China
Published online on: March 28, 2014 https://doi.org/10.3892/mmr.2014.2087
Pages: 2453-2458

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Dominant mutations in superoxide dismutase 1 (SOD1) are a frequent cause of the lethal neurodegenerative disease amyotrophic lateral sclerosis (ALS). The nuclear factor erythroid 2‑related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is the major cellular defense mechanism against oxidative stress, however, its role in ALS remains to be fully elucidated. Therefore, the present study aimed to investigate whether the human SOD1‑G93A gene affected the Nrf2/ARE signaling pathway in an ALS cell model. The soma became round and the number of neurites decreased in the NSC‑34 cells transfected with the hSOD1‑G93A gene, and the neurites were shorter and oxidative stress was increased compared with the normal NSC‑34 cells. Furthermore, the mRNA and protein expression of Nrf2, heme oxygenase‑1 and NAD(P)H: quinone oxidoreductase 1 was significantly decreased in the NSC‑34 cells transfected with the human SOD1‑G93A gene. The present study indicated that human SOD1‑G93A damaged the Nrf2/ARE signaling pathway in the ALS cell model and reduced the ability of cells to protect against oxidative injury.

View Figures

View References

1	Avossa D, Grandolfo M, Mazzarol F, et al: Early signs of motoneuron vulnerability in a disease model system: characterization of transverse slice cultures of spinal cord isolated from embryonic ALS mice. Neuroscience. 138:1179–1194. 2006. View Article : Google Scholar : PubMed/NCBI
2	Mitchell JD, Callagher P, Gardham J, et al: Timelines in the diagnostic evaluation of people with suspected amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND) - a 20-year review: can we do better? Amyotroph Lateral Scler. 11:537–541. 2010.PubMed/NCBI
3	Kiernan MC, Vucic S, Cheah BC, et al: Amyotrophic lateral sclerosis. Lancet. 377:942–955. 2011. View Article : Google Scholar
4	Zinman L and Cudkowicz M: Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet Neurology. 10:481–490. 2011. View Article : Google Scholar : PubMed/NCBI
5	Barber SC and Shaw PJ: Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Radical Biol Med. 48:629–641. 2010. View Article : Google Scholar : PubMed/NCBI
6	Petri S, Körner S and Kiaei M: Nrf2/ARE signaling pathway: key mediator in oxidative stress and potential therapeutic target in ALS. Neurol Res Int. 2012:8780302012. View Article : Google Scholar : PubMed/NCBI
7	Valdmanis PN, Daoud H, Dion PA and Rouleau GA: Recent advances in the genetics of amyotrophic lateral sclerosis. Curr Neurol Neurosci Rep. 9:198–205. 2009. View Article : Google Scholar : PubMed/NCBI
8	Howland DS, Liu J, She Y, et al: Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). Proc Natl Acad Sci USA. 99:1604–1609. 2002. View Article : Google Scholar : PubMed/NCBI
9	Gurney ME, Pu H, Chiu AY, et al: Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science. 264:1772–1775. 1994. View Article : Google Scholar
10	Yu X and Kensler T: Nrf2 as a target for cancer chemoprevention. Mutat Res. 591:93–102. 2005. View Article : Google Scholar : PubMed/NCBI
11	Taguchi K, Motohashi H and Yamamoto M: Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 16:123–140. 2011. View Article : Google Scholar : PubMed/NCBI
12	Vargas MR and Johnson JA: The Nrf2-ARE cytoprotective pathway in astrocytes. Expert Rev Mol Med. 11:e172009. View Article : Google Scholar : PubMed/NCBI
13	Hybertson BM, Gao B, Bose SK and McCord JM: Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Aspects Med. 32:234–246. 2011. View Article : Google Scholar : PubMed/NCBI
14	Mariani E, Polidori MC, Cherubini A and Mecocci P: Oxidative stress in brain aging, neurodegenerative and vascular diseases: an overview. J Chromatogr B Analyt Technol Biomed Life Sci. 827:65–75. 2005. View Article : Google Scholar : PubMed/NCBI
15	Shibata N, Nagai R, Uchida K, et al: Morphological evidence for lipid peroxidation and protein glycoxidation in spinal cords from sporadic amyotrophic lateral sclerosis patients. Brain Res. 917:97–104. 2001. View Article : Google Scholar
16	Sarlette A, Krampfl K, Grothe C, et al: Nuclear erythroid 2-related factor 2-antioxidative response element signaling pathway in motor cortex and spinal cord in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 67:1055–1062. 2008. View Article : Google Scholar
17	Pehar M, Vargas MR, Robinson KM, et al: Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J Neurosci. 27:7777–7785. 2007. View Article : Google Scholar
18	Neymotin A, Calingasan NY, Wille E, et al: Neuroprotective effect of Nrf2/ARE activators, CDDO ethylamide and CDDO trifluoroethylamide, in a mouse model of amyotrophic lateral sclerosis. Free Radic Biol Med. 51:88–96. 2011. View Article : Google Scholar : PubMed/NCBI
19	Malhotra D, Portales-Casamar E, Singh A, et al: Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res. 38:5718–5734. 2010. View Article : Google Scholar : PubMed/NCBI
20	Poss KD and Tonegawa S: Reduced stress defense in heme oxygenase 1-deficient cells. Proc Natl Acad Sci USA. 94:10925–10930. 1997. View Article : Google Scholar : PubMed/NCBI
21	Siegel D, Gustafson DL, Dehn DL, et al: NAD(P)H:quinone oxidoreductase 1: role as a superoxide scavenger. Mol Pharmacol. 65:1238–1247. 2004. View Article : Google Scholar : PubMed/NCBI
22	Slocum SL and Kensler TW: Nrf2: control of sensitivity to carcinogens. Arch Toxicol. 85:273–284. 2011. View Article : Google Scholar : PubMed/NCBI
23	Vargas MR, Burton NC, Kutzke J, et al: Absence of Nrf2 or its selective overexpression in neurons and muscle does not affect survival in ALS-linked mutant hSOD1 mouse models. PLoS One. 8:e566252013. View Article : Google Scholar : PubMed/NCBI
24	Sun MM, Bu H, Li B, et al: Neuroprotective potential of phase II enzyme inducer diallyl trisulfide. Neurol Res. 31:23–27. 2009. View Article : Google Scholar : PubMed/NCBI
25	Stack C, Ho D, Wille E, et al: Triterpenoids CDDO-ethyl amide and CDDO-trifluoroethyl amide improve the behavioral phenotype and brain pathology in a transgenic mouse model of Huntington’s disease. Free Radic Biol Med. 49:147–158. 2010.PubMed/NCBI