Abstract
Iron plays a key role in Parkinson's disease (PD). Increased iron content of the substantia nigra (SN) has been found in PD patients, and divalent metal transporter 1 (DMT1) has been shown to be up-regulated in the SN of both MPTP-induced PD models and PD patients. However, the mechanisms underlying DMT1 up-regulation are largely unknown. In the present study, we observed that in the SN of 6-hydroxydopamine (6-OHDA)-induced PD rats, DMT1 with the iron responsive element (IRE, DMT1+IRE), but not DMT1 without IRE (DMT1−IRE), was up-regulated, suggesting that increased DMT1+IRE expression might account for nigral iron accumulation in PD rats. This possibility was further assessed in an in vitro study using 6-OHDA-treated and DMT1+IRE-over-expressing MES23.5 cells. In 6-OHDA-treated MES23.5 cells, increased iron regulatory protein (IRP) 1 and IRP2 expression was observed, while silencing of IRPs dramatically diminished 6-OHDA-induced DMT1+IRE up-regulation. Pretreatment with N-acetyl-L-cysteine fully suppressed IRPs up-regulation by inhibition of 6-OHDA-induced oxidative stress. Increased DMT1+IRE expression resulted in increased iron influx by MES23.5 cells. Our data provide direct evidence that DMT1+IRE up-regulation can account for IRE/IRP-dependent 6-OHDA-induced iron accumulation initiated by 6-OHDA-induced intracellular oxidative stress and that increased levels of intracellular iron result in aggravated oxidative stress. The results of this study provide novel evidence supporting the use of anti-oxidants in the treatment of PD, with the goal of inhibiting iron accumulation by regulation of DMT1 expression.
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Abbreviations
- DFO:
-
(desferrioxamine mesylate)
- DMT1:
-
(divalent metal transporter 1);)
- HBS:
-
(HEPES-buffered saline)
- 6-OHDA:
-
(6-hydroxydopamine)
- IRE:
-
(iron response element)
- IRP:
-
(iron regulatory protein)
- ΔΨm:
-
(mitochondrial transmembrane potential)
- NAC:
-
(N-acetyl-L-cysteine)
- PD:
-
(Parkinson's disease)
- PBS:
-
(phosphate-buffered saline)
- ROS:
-
(reactive oxygen species)
- siRNA:
-
(small interfering RNA)
- SN:
-
(substantia nigra)
- TfR1:
-
(transferrin receptor 1)
- UTR:
-
(untranslated region)
- MPTP:
-
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
- MPP+:
-
(1-methyl-4-phenylpyridinium)
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Acknowledgements
We thank Dr Wei-dong Le for providing the MES23.5 cell line. This work was supported by grants from the National Program of Basic Research sponsored by the Ministry of Science and Technology of China (2006CB500704), the National Natural Science Foundation of China (30930036, 30770757, 30870858) and the Natural Science Fund of Shandong Province for Distinguished Young Scholars (JQ200807).
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Jiang, H., Song, N., Xu, H. et al. Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res 20, 345–356 (2010). https://doi.org/10.1038/cr.2010.20
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DOI: https://doi.org/10.1038/cr.2010.20
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