Item

ITEM ACTIONS

Please note that a newer version of this item is available:
https://pure.mpg.de/pubman/item/item_2634483_5

This item is discarded!Release HistoryDetailsSummary

Discarded

Journal Article

S-nitrosylation of divalent metal transporter 1 enhances iron uptake to mediate loss of dopaminergic neurons and motoric deficit

MPS-Authors

/persons/resource/persons14947

Chua, J. J. E.
Research Group of Protein Trafficking in Synaptic Development and Function, MPI for Biophysical Chemistry, Max Planck Society;

External Resource

No external resources are shared

Fulltext (restricted access)

There are currently no full texts shared for your IP range.

Fulltext (public)

There are no public fulltexts stored in PuRe

Supplementary Material (public)

There is no public supplementary material available

Citation

Liu, C., Zhang, C.-W., Lo, S. Q., Ang, S. T., Chew, K. C. M., Yu, D., et al. (2018). S-nitrosylation of divalent metal transporter 1 enhances iron uptake to mediate loss of dopaminergic neurons and motoric deficit. Journal of Neuroscience, in press. doi:10.1523/JNEUROSCI.3262-17.2018.

Abstract

Elevated iron deposition has been reported in Parkinson's disease. However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe2+ uptake via S-nitrosylation of DMT1. While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in post-mortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn2+ or Fe2+ uptake through S-nitrosylated DMT1. We identified two major S-nitrosylation sites, C23 and C540, by mass spectrometry and DMT1 C23A or C540A substitutions abolished NO-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral lipopolysaccharide injection resulted in corresponding increase in Fe2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by NOS inhibitor, L-NAME, or by DMT1-selective blocker, ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.