Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS

Pamela Milani, Marialaura Amadio, Umberto Laforenza, Michela Dell'Orco, Luca Diamanti, Valentina Sardone, Stella Gagliardi, Stefano Govoni, Mauro Ceroni, Alessia Pascale, Cristina Cereda

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Increased levels of SOD1 mRNA have been observed in sporadic ALS patients (SALS) compared to controls. Hence, the understanding of the mechanisms by which SOD1 gene expression is modulated may shed new light on SOD1 involvement in ALS. Of interest, some adenine/uracil-rich elements (AREs) in SOD1 3'-untranslated region have been identified. These sequences represent the docking sites for several RNA-binding proteins such as ELAV proteins (ELAVs), positive regulators of gene expression. We first investigated in SH-SY5Y cells whether SOD1 mRNA represents a target of ELAVs. Results from RNA Electrophoretic Mobility Shift and RNA-immunoprecipitation assays showed a molecular interaction between ELAVs and SOD1 mRNA. We also observed that the treatment with H2O2 induced a significant increase of the amount of SOD1 mRNA bound by ELAVs and an up-regulation of SOD1 protein levels. We found a specific increase in ELAV/HuR phosphorylation, suggesting activation of this protein, in peripheral blood mononuclear cells from SALS patients compared to controls. Finally, we found increased levels of ELAV proteins in the motor cortex and spinal cord from SALS patients compared to controls, in parallel with SOD1 up-regulation in the same areas. This study suggests, for the first time, that ELAVs are involved in the regulation of SOD1 gene expression at post-transcriptional level and that these proteins are more activated in ALS pathology. The link between ELAVs and SOD1 may open novel perspectives for ALS research, paving the way for new therapeutic options.

Original languageEnglish
Pages (from-to)51-60
Number of pages10
JournalNeurobiology of Disease
Volume60
DOIs
Publication statusPublished - Dec 2013

Fingerprint

ELAV Proteins
Gene Expression Regulation
Oxidative Stress
Messenger RNA
Up-Regulation
RNA
Gene Expression
RNA-Binding Proteins
Uracil
Motor Cortex
3' Untranslated Regions
Adenine
Regulator Genes
Immunoprecipitation
Blood Cells
Spinal Cord
Proteins
Phosphorylation
Pathology
Therapeutics

Keywords

  • ELAV proteins
  • Motor cortex
  • MRNA
  • Peripheral blood mononuclear cells
  • Posttranscriptional regulation
  • SOD1
  • Spinal cord
  • Sporadic amyotrophic lateral sclerosis

ASJC Scopus subject areas

  • Neurology

Cite this

Posttranscriptional regulation of SOD1 gene expression under oxidative stress : Potential role of ELAV proteins in sporadic ALS. / Milani, Pamela; Amadio, Marialaura; Laforenza, Umberto; Dell'Orco, Michela; Diamanti, Luca; Sardone, Valentina; Gagliardi, Stella; Govoni, Stefano; Ceroni, Mauro; Pascale, Alessia; Cereda, Cristina.

In: Neurobiology of Disease, Vol. 60, 12.2013, p. 51-60.

Research output: Contribution to journalArticle

Milani, Pamela ; Amadio, Marialaura ; Laforenza, Umberto ; Dell'Orco, Michela ; Diamanti, Luca ; Sardone, Valentina ; Gagliardi, Stella ; Govoni, Stefano ; Ceroni, Mauro ; Pascale, Alessia ; Cereda, Cristina. / Posttranscriptional regulation of SOD1 gene expression under oxidative stress : Potential role of ELAV proteins in sporadic ALS. In: Neurobiology of Disease. 2013 ; Vol. 60. pp. 51-60.
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AU - Sardone, Valentina

AU - Gagliardi, Stella

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AB - Increased levels of SOD1 mRNA have been observed in sporadic ALS patients (SALS) compared to controls. Hence, the understanding of the mechanisms by which SOD1 gene expression is modulated may shed new light on SOD1 involvement in ALS. Of interest, some adenine/uracil-rich elements (AREs) in SOD1 3'-untranslated region have been identified. These sequences represent the docking sites for several RNA-binding proteins such as ELAV proteins (ELAVs), positive regulators of gene expression. We first investigated in SH-SY5Y cells whether SOD1 mRNA represents a target of ELAVs. Results from RNA Electrophoretic Mobility Shift and RNA-immunoprecipitation assays showed a molecular interaction between ELAVs and SOD1 mRNA. We also observed that the treatment with H2O2 induced a significant increase of the amount of SOD1 mRNA bound by ELAVs and an up-regulation of SOD1 protein levels. We found a specific increase in ELAV/HuR phosphorylation, suggesting activation of this protein, in peripheral blood mononuclear cells from SALS patients compared to controls. Finally, we found increased levels of ELAV proteins in the motor cortex and spinal cord from SALS patients compared to controls, in parallel with SOD1 up-regulation in the same areas. This study suggests, for the first time, that ELAVs are involved in the regulation of SOD1 gene expression at post-transcriptional level and that these proteins are more activated in ALS pathology. The link between ELAVs and SOD1 may open novel perspectives for ALS research, paving the way for new therapeutic options.

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