Hydrogen peroxide-mediated induction of SOD1 gene transcription is independent from Nrf2 in a cellular model of neurodegeneration

Michela Dell'Orco, Pamela Milani, Laura Arrigoni, Orietta Pansarasa, Valentina Sardone, Elisa Maffioli, Francesca Polveraccio, Matteo Bordoni, Luca Diamanti, Mauro Ceroni, Fiorenzo A. Peverali, Gabriellla Tedeschi, Cristina Cereda

Research output: Contribution to journalArticle

Abstract

Background: It is still unclear whether oxidative stress (OS) is a disease consequence or is directly involved in the etiology of neurodegenerative disorders (NDs) onset and/or progression; however, many of these conditions are associated with increased levels of oxidation markers and damaged cell components. Previously we demonstrated the accumulation of reactive oxygen species (ROS) and increased SOD1 gene expression in H2O2-treated SH-SY5Y cells, recapitulating pathological features of Amyotrophic Lateral Sclerosis (ALS). Since we observed a post-transcriptional regulation of SOD1 gene in this cellular model, we investigated the transcriptional regulation of SOD1 mRNA under oxidative stress (OS). Results: In response to H2O2 treatment, PolII increased its association to SOD1 promoter. Electrophoretic mobility shift assays and mass spectrometry analyses on SOD1 promoter highlighted the formation of a transcriptional complex bound to the ARE sequences. Western Blotting experiments showed that in our in vitro model, H2O2 exposure increases Nrf2 expression in the nuclear fraction while immunoprecipitation confirmed its phosphorylation and release from Keap1 inhibition. However, H2O2 treatment did not modify Nrf2 binding on SOD1 promoter, which seems to be regulated by different transcription factors (TFs). Conclusions: Although our data suggest that SOD1 is transcriptionally regulated in response to OS, Nrf2 does not appear to associate with SOD1 promoter in this cellular model of neurodegeneration. Our results open new perspectives in the comprehension of two key antioxidant pathways involved in neurodegenerative disorders.

Original languageEnglish
Pages (from-to)315-323
Number of pages9
JournalBiochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume1859
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Keywords

  • Neurodegeneration
  • Nrf2
  • Oxidative stress
  • SOD1
  • Transcriptional regulation

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Genetics
  • Molecular Biology
  • Structural Biology

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