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 language | English |
|---|---|
| Pages (from-to) | 51-60 |
| Number of pages | 10 |
| Journal | Neurobiology of Disease |
| Volume | 60 |
| DOIs | |
| Publication status | Published - Dec 2013 |
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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 journal › Article
}
TY - JOUR
T1 - Posttranscriptional regulation of SOD1 gene expression under oxidative stress
T2 - Potential role of ELAV proteins in sporadic ALS
AU - Milani, Pamela
AU - Amadio, Marialaura
AU - Laforenza, Umberto
AU - Dell'Orco, Michela
AU - Diamanti, Luca
AU - Sardone, Valentina
AU - Gagliardi, Stella
AU - Govoni, Stefano
AU - Ceroni, Mauro
AU - Pascale, Alessia
AU - Cereda, Cristina
PY - 2013/12
Y1 - 2013/12
N2 - 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.
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.
KW - ELAV proteins
KW - Motor cortex
KW - MRNA
KW - Peripheral blood mononuclear cells
KW - Posttranscriptional regulation
KW - SOD1
KW - Spinal cord
KW - Sporadic amyotrophic lateral sclerosis
UR - http://www.scopus.com/inward/record.url?scp=84883648450&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84883648450&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.08.005
DO - 10.1016/j.nbd.2013.08.005
M3 - Article
C2 - 23969235
AN - SCOPUS:84883648450
VL - 60
SP - 51
EP - 60
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -