Nuclear Factor Erythroid 2-Related Factor 2 as a Gene Modulator of Response to Oxidative Stress in Amyotrophic Lateral Sclerosis - European Medical Journal

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Nuclear Factor Erythroid 2-Related Factor 2 as a Gene Modulator of Response to Oxidative Stress in Amyotrophic Lateral Sclerosis

1 Mins
Neurology
Authors:
Annalisa Lo Gerfo,1 Costanza Simoncini,1 Lucia Chico,1 Vincenzo Montano,1 Cecilia Carlesi,1 Filippo Baldacci,1 Simona Daniele,2 Maria Rosaria Maluccio,3 Giulia Ricci,1 Michelangelo Mancuso,1 Gabriele Siciliano1

Department of Clinical and Experimental Medicine, University of Pisa, Italy
Department of Pharmacy, University of Pisa, Italy
Clinic of Neurology, Department of Clinical Medicine, ATNO, Italy

Disclosure:

The authors have declared no conflicts of interest.

Keywords:
Amyotrophic lateral sclerosis (ALS), Nrf2–ARE pathway, oxidative stress (OS), therapeutic target. Citation: EMJ Neurol. 2019;7[1]:40-41 Abstract Review No. AR1.

Each article is made available under the terms of the Creative Commons Attribution-Non Commercial 4.0 License.

BACKGROUND AND AIM

Among the pathogenic mechanisms on motor neuron degeneration leading to amyotrophic lateral sclerosis (ALS), the oxidative stress (OS) theory has been put forward.1 Although it remains hard to understand whether or not OS is the cause or effect of the disease, the association between oxidative damage and the disease makes therapeutic targeting of the antioxidant systems an attractive option.2,3 Nuclear factor Erythroid 2-related factor 2 (Nrf2)–anti-oxidant response elements (ARE) pathway is a primary sensor and a master regulator of OS via its ability to modulate the expression of hundreds of antioxidant genes.4,5 Considering the pivotal defensive role exerted by the Nrf2–ARE pathway (demonstrated in animal models of many neurodegenerative disorders), it is evident that the dysregulation of Nrf2-regulated genes offers a possible explanation for the direct and indirect association between OS and ALS.6-8 This work was aimed to evaluate a possible association between -653 A>G, -651 G>A, and -617 C>A functional polymorphisms in the NRF2 promoter gene with the NRF2 mRNA and OS biomarkers in ALS.

RESULTS

Analysis of 150 ALS patient’s data showed that the allelic -653G variant is associated with increased risk of disease (odds ratio: 1.71; 95% confidence interval: 1.18–2.48); in relation to the polymorphisms -651 G>A and -617 C>A, no significant differences have been found in either the genotypic distribution or in the allelic frequencies of patients with ALS compared to the controls. The evaluation of peripheral OS biomarkers showed a significant increase in advanced protein oxidation products (AOPP) levels (p<0.001) and a significant decrease in thiol groups (-SH) levels (p<0.01) in ALS patients; the authors did not find any imbalance in the Iron-reducing capacity of plasma (FRAP) level of ALS patients compared to controls. mRNA expression in ALS lymphocytes carrying -653 AG or -653 GG genotype was significantly decreased (p>0.05) compared to wildtype (AA) carriers at this position. Finally, the data obtained showed a correlation between the -653G variant, mRNA expression level, and OS biomarkers in ALS patients.

CONCLUSIONS

The data obtained suggest that the -653G variant in Nrf2 promoter gene can be a risk factor for ALS. This variant is associated to decreased level of Nrf2 mRNA as evaluated in peripheral lymphocytes. All together these data reinforce the statement that the Nrf2–ARE pathway can be one of the pathogenic molecular mechanisms to be considered in motoneuron neurodegeneration in ALS. Conclusive remarks can be assumed in terms of relevance of OS events as integral part of the pathogenic complex of this disease.

References
Cozzolino E et al. Amyotrophic lateral sclerosis: New insights into underlying molecular mechanisms and opportunities for therapeutic intervention. Antioxid Redox Signal. 2012;17(9):1277-330. Rossi et al. Altered gene expression, mitochondrial damage and oxidative stress: Converging routes in motor neuron degeneration. Int J Cell Biol. 2012;2012:908724. Strong MJ. The evidence for altered RNA metabolism in amyotrophic lateral sclerosis (ALS). J Neurol Sci. 2010;288(1-2):1-12. Dinkova-Kostova AT et al. The spatiotemporal regulation of the Keapl–Nrf2 pathway and its importance in cellular bioenergetics. Biochem Soc Trans. 2015;43(4):602-10. Bonnefont-Rousselot D et al. Blood oxidative stress in amyotrophic lateral sclerosis. J Neurol Sci. 2000;178(1):57-62. Johnson DA et al. The absence of the pro-antioxidant transcription factor Nrf2 exacerbates experimental autoimmune encephalomyelitis. Toxicol Sci. 2010;114(2):236-46. von Otter M et al. Association of Nrf2-encoding NFE2L2 haplotypes with Parkinson’s disease. BMC Med Genet. 2010;11:36. Bergström P et al. Association of NFE2L2 and KEAPI haplotypes with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15(1-2):130-7.

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