Abstract
Exposure to excessive manganese (Mn) causes manganism, a progressive neurodegenerative disorder similar to idiopathic Parkinson’s disease (IPD). The detailed mechanisms of Mn neurotoxicity in nerve cells, especially in dopaminergic neurons are not yet fully understood. Meanwhile, it is unknown whether there exists a potential antagonist or effective drug for treating neuron damage in manganism. In the present study, we report the discovery of an HIF prolyl-hydroxylase inhibitor, DMOG [N-(2-Methoxy-2-oxoacetyl) glycine methyl ester], that can partially inhibit manganese toxicity not only in the neuroblastoma cell line SH-SY5Y in vitro but also in a mouse model in vivo. A genome-wide methylation DNA analysis was performed using microarray hybridization. Intriguingly, DNA methylation in the promoter region of 226 genes was found to be regulated by MnCl2, while the methylation effects of MnCl2 could be restored with combinatorial DMOG treatment. Furthermore, we found that genes with converted promoter methylation during DMOG antagonism were associated across several categories of molecular function, including mitochondria integrity maintain, cell cycle and DNA damage response, and ion transportation. Collectively, our results serve as the basis of a mechanism analysis of neuron damage in manganism and may supply possible gene targets for clinical therapy.
Highlights
Parkinson’s disease (PD) is a progressive disorder of the nervous system that mainly occurs in elderly individuals
For the first time, we reveal the antagonistic effects of DMOG, an Hypoxia-inducible factor 1 (HIF-1) prolyl-hydroxylase inhibitor on the cytotoxicity caused by excessive manganese exposure in the human neuroblastoma cell line SH-SY5Y in vitro and in the substantia nigra of the mouse brain in vivo
Pre-treatment with DMOG of 3 mM to 4.5 mM dramatically increased the viability of SH-SY5Y cells to 60–65%, and the highest live cell percentage was observed at 4 mM of DMOG treatment
Summary
Parkinson’s disease (PD) is a progressive disorder of the nervous system that mainly occurs in elderly individuals. When oxygen concentrations are reduced (hypoxia), the normal degradation of HIF-1αis inhibited, leading to increased protein levels of HIF-1αand the formation of an HIF-1 protein dimer This activated HIF-1 recruits coactivator protein, binds the cis-response element together and participates in the transcriptional regulation of target gene[15]. Overexpression of ATP13A2 antagonizes the cytotoxicity caused by excessive Mn exposure[23] These results suggest that HIF-1 and its corresponding pathways might be potential therapeutic targets in various neurodegenerative diseases. Research into the epigenetics caused by environmental exposure will undoubtedly uncover the biological significance of environmental factors in diseases, including manganism or PD caused by excessive manganese exposure, and the regulations of genes expression caused by promoter methylation during the processes of corresponding therapies for manganism are attractive
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