title: Posttranscriptional regulation of SOD1 gene expression under oxidative stress: Potential role of ELAV proteins in sporadic ALS.
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.
authors: Laboratory of Experimental Neurobiology, "C. Mondino" National Institute of Neurology Foundation, IRCCS, Via Mondino 2, 27100 Pavia, Italy; Department of Public Health, Neuroscience, Experimental and Forensic Medicine, University of Pavia, Via Ferrata 9, 27100 Pavia, Italy. Electronic address: pame.milani@gmail.com.
authors: Pamela
authors: P
authors: Milani
authors: Marialaura
authors: M
authors: Amadio
authors: Umberto
authors: U
authors: Laforenza
authors: Michela
authors: M
authors: Dell'Orco
authors: Luca
authors: L
authors: Diamanti
authors: Valentina
authors: V
authors: Sardone
authors: Stella
authors: S
authors: Gagliardi
authors: Stefano
authors: S
authors: Govoni
authors: Mauro
authors: M
authors: Ceroni
authors: Alessia
authors: A
authors: Pascale
authors: Cristina
authors: C
authors: Cereda
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D051959:ELAV Proteins / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000235:genetics*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000072105:Superoxide Dismutase-1
chemical_list: D051959:ELAV Proteins; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: ELAV proteins; Motor cortex; Peripheral blood mononuclear cells; Posttranscriptional regulation; SOD1; Spinal cord; Sporadic amyotrophic lateral sclerosis; mRNA