Abstract
| Original language | English |
|---|---|
| Journal | Frontiers in Neuroscience |
| Volume | 11 |
| Issue number | JAN |
| DOIs | |
| Publication status | Published - 2017 |
Keywords
- BDNF
- HDAC4
- MeHg
- Neuronal cell death
- P38
- Sp transcription factors
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p38/Sp1/Sp4/HDAC4/BDNF axis is a novel molecular pathway of the neurotoxic effect of the methylmercury. / Guida, N.; Laudati, Guisy; Mascolo, Luigi; Valsecchi, V.; Sirabella, R.; Selleri, C.; Di Renzo, G.; Canzoniero, Lorella M T; Formisano, Luigi.
In: Frontiers in Neuroscience, Vol. 11, No. JAN, 2017.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - p38/Sp1/Sp4/HDAC4/BDNF axis is a novel molecular pathway of the neurotoxic effect of the methylmercury
AU - Guida, N.
AU - Laudati, Guisy
AU - Mascolo, Luigi
AU - Valsecchi, V.
AU - Sirabella, R.
AU - Selleri, C.
AU - Di Renzo, G.
AU - Canzoniero, Lorella M T
AU - Formisano, Luigi
N1 - Export Date: 21 March 2017 Correspondence Address: Formisano, L.; Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, 'Federico II' University of NaplesItaly; email: cformisa@unisannio.it References: Bardai, F.H., D'Mello, S.R., Selective toxicity by HDAC3 in neurons: regulation by Akt and GSK3β (2011) J. Neurosci, 31, pp. 1746-1751; Bolger, T.A., Yao, T.P., Intracellular trafficking of histone deacetylase 4 regulates neuronal cell death (2005) J. Neurosci, 25, pp. 9544-9553; Ceccatelli, S., Bose, R., Edoff, K., Onishchenko, N., Spulber, S., Long-lasting neurotoxic effects of exposure to methylmercury during development (2013) J. Intern. Med, 273, pp. 490-497; de Nigris, F., Crudele, V., Giovane, A., Casamassimi, A., Giordano, A., Garban, H.J., CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy (2010) Proc. Natl. Acad. Sci. 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Ther, 338, pp. 518-527; Koppel, I., Timmusk, T., Differential regulation of Bdnf expression in cortical neurons by class-selective histone deacetylase inhibitors (2013) Neuropharmacology, 75, pp. 106-115; Liu, F., Pore, N., Kim, M., Voong, K.R., Dowling, M., Maity, A., Regulation of histone deacetylase 4 expression by the SP family of transcription factors (2006) Mol. Biol. Cell, 17, pp. 585-597; Lu, T.H., Hsieh, S.Y., Yen, C.C., Wu, H.C., Chen, K.L., Hung, D.Z., Involvement of oxidative stress-mediated ERK1/2 and p38 activation regulated mitochondria-dependent apoptotic signals in methylmercury-induced neuronal cell injury (2011) Toxicol. Lett, 204, pp. 71-80; Myers, G.J., Davidson, P.W., Prenatal methylmercury exposure and children: neurologic, developmental, and behavioral research (1998) Environ. Health Perspect, 106, pp. 841-847; Nagahara, A.H., Merrill, D.A., Coppola, G., Tsukada, S., Schroeder, B.E., Shaked, G.M., Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease (2009) Nat. Med, 15, pp. 331-337; Ni, M., Li, X., Yin, Z., Sidoryk-Wegrzynowicz, M., Jiang, H., Farina, M., Comparative study on the response of rat primary astrocytes and microglia to methylmercury toxicity (2011) Glia, 59, pp. 810-820; Posser, T., Dunkley, P.R., Dickson, P.W., Franco, J.L., Human neuroblastoma cells transfected with tyrosine hydroxylase gain increased resistance to methylmercury-induced cell death (2010) Toxicol. In Vitro, 24, pp. 1498-1503; Qiu, Z., Norflus, F., Singh, B., Swindell, M.K., Buzescu, R., Bejarano, M., Sp1 is up-regulated in cellular and transgenic models of Huntington disease, and its reduction is neuroprotective (2006) J. Biol. 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Sci, 40, pp. 817-828; Sirabella, R., Secondo, A., Pannaccione, A., Molinaro, P., Formisano, L., Guida, N., ERK1/2, p38, and JNK regulate the expression and the activity of the three isoforms of the Na+/Ca2+ exchanger, NCX1, NCX2, and NCX3, in neuronal PC12 cells (2012) J. Neurochem, 122, pp. 911-922; Spulber, S., Rantamäki, T., Nikkilä, O., Castrén, E., Weihe, P., Grandjean, P., Effects of maternal smoking and exposure to methylmercury on brain-derived neurotrophic factor concentrations in umbilical cord serum (2010) Toxicol. Sci, 117, pp. 263-269; Suske, G., The Sp-family of transcription factors (1999) Gene, 238, pp. 291-300; Tao, X., Finkbeiner, S., Arnold, D.B., Shaywitz, A.J., Greenberg, M.E., Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism (1998) Neuron, 20, pp. 709-726; Vinciguerra, A., Formisano, L., Cerullo, P., Guida, N., Cuomo, O., Esposito, A., MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by Anti-miRNA ameliorates stroke damage and neurological deficits (2014) Mol. 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PY - 2017
Y1 - 2017
N2 - The molecular pathways involved in methylmercury (MeHg)-induced neurotoxicity are not fully understood. Since pan-Histone deacetylases (HDACs) inhibition has been found to revert the neurodetrimental effect of MeHg, it appeared of interest to investigate whether the pattern of HDACs isoform protein expression is modified during MeHg-induced neurotoxicity and the transcriptional/transductional mechanisms involved. SH-SY5Y neuroblastoma cells treated with MeHg 1 μM for 12 and 24 h showed a significant increase of HDAC4 protein and gene expression, whereas the HDACs isoforms 1-3, 5, and 6 were unmodified. Furthermore, MeHg-induced HDAC4 increase was reverted when cells were transfected with siRNAs against specificity protein 1 (Sp1) and Sp4, that were both increased during MeHg exposure. Next we studied the role of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) in MeHg-induced increase of Sp1, Sp4, and HDAC4 expression. As shown by Western Blot analysis MeHg exposure increased the phosphorylation of p38, but not of ERK and JNK. Notably, when p38 was pharmacologically blocked, MeHg-induced Sp1, Sp4 protein expression, and HDAC4 protein and gene expression was reverted. In addition, MeHg exposure increased the binding of HDAC4 to the promoter IV of the Brain-derived neurotrophic factor (BDNF) gene, determining its mRNA reduction, that was significantly counteracted by HDAC4 knocking down. Furthermore, rat cortical neurons exposed to MeHg (1 μM/24 h) showed an increased phosphorylation of p38, in parallel with an up-regulation of Sp1, Sp4, and HDAC4 and a down-regulation of BDNF proteins. Importantly, transfection of siRNAs against p38, Sp1, Sp4, and HDAC4 or transfection of vector overexpressing BDNF significantly blocked MeHg-induced cell death in cortical neurons. All these results suggest that p38/Sp1-Sp4/HDAC4/BDNF may represent a new pathway involved in MeHg-induced neurotoxicity. © 2017 Guida, Laudati, Mascolo, Valsecchi, Sirabella, Selleri, Di Renzo, Canzoniero and Formisano.
AB - The molecular pathways involved in methylmercury (MeHg)-induced neurotoxicity are not fully understood. Since pan-Histone deacetylases (HDACs) inhibition has been found to revert the neurodetrimental effect of MeHg, it appeared of interest to investigate whether the pattern of HDACs isoform protein expression is modified during MeHg-induced neurotoxicity and the transcriptional/transductional mechanisms involved. SH-SY5Y neuroblastoma cells treated with MeHg 1 μM for 12 and 24 h showed a significant increase of HDAC4 protein and gene expression, whereas the HDACs isoforms 1-3, 5, and 6 were unmodified. Furthermore, MeHg-induced HDAC4 increase was reverted when cells were transfected with siRNAs against specificity protein 1 (Sp1) and Sp4, that were both increased during MeHg exposure. Next we studied the role of extracellular-signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 mitogen-activated protein kinases (MAPKs) in MeHg-induced increase of Sp1, Sp4, and HDAC4 expression. As shown by Western Blot analysis MeHg exposure increased the phosphorylation of p38, but not of ERK and JNK. Notably, when p38 was pharmacologically blocked, MeHg-induced Sp1, Sp4 protein expression, and HDAC4 protein and gene expression was reverted. In addition, MeHg exposure increased the binding of HDAC4 to the promoter IV of the Brain-derived neurotrophic factor (BDNF) gene, determining its mRNA reduction, that was significantly counteracted by HDAC4 knocking down. Furthermore, rat cortical neurons exposed to MeHg (1 μM/24 h) showed an increased phosphorylation of p38, in parallel with an up-regulation of Sp1, Sp4, and HDAC4 and a down-regulation of BDNF proteins. Importantly, transfection of siRNAs against p38, Sp1, Sp4, and HDAC4 or transfection of vector overexpressing BDNF significantly blocked MeHg-induced cell death in cortical neurons. All these results suggest that p38/Sp1-Sp4/HDAC4/BDNF may represent a new pathway involved in MeHg-induced neurotoxicity. © 2017 Guida, Laudati, Mascolo, Valsecchi, Sirabella, Selleri, Di Renzo, Canzoniero and Formisano.
KW - BDNF
KW - HDAC4
KW - MeHg
KW - Neuronal cell death
KW - P38
KW - Sp transcription factors
U2 - 10.3389/fnins.2017.00008
DO - 10.3389/fnins.2017.00008
M3 - Article
VL - 11
JO - Frontiers in Neuroscience
JF - Frontiers in Neuroscience
SN - 1662-4548
IS - JAN
ER -