Please use this identifier to cite or link to this item: https://doi.org/10.1523/JNEUROSCI.3262-17.2018
Title: S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit
Authors: Liu, Chao 
Zhang, Cheng-Wu 
Lo, Shun Qiang 
Ang, Seok Ting 
Chew, Katherine Chee Meng 
Yu, Dejie
Chai, Bing Han
Tan, Bobby
Tsang, Fai 
Tai, Yee Kit 
Tan, Bryce Wei Quan
Liang, Mui Cheng 
Tan, Hwee Tong 
Tang, Jia Ying 
Lai, Mitchell Kim Peng 
Chua, John Jia En 
Chung, Maxey Ching Ming 
Khanna, Sanjay 
Lim, Kah-Leong 
Soong, Tuck Wah 
Keywords: Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
DMT1
dopaminergic neurons
iron deposition
motoric defects
nitric oxide
S-nitrosylation
RESIN-ASSISTED CAPTURE
NITRIC-OXIDE SYNTHASE
PARKINSONS-DISEASE
SUBSTANTIA-NIGRA
BINDING PROTEIN
UP-REGULATION
RAT-BRAIN
IN-VIVO
NEURODEGENERATION
MICROGLIA
Issue Date: 26-Sep-2018
Publisher: SOC NEUROSCIENCE
Citation: Liu, Chao, Zhang, Cheng-Wu, Lo, Shun Qiang, Ang, Seok Ting, Chew, Katherine Chee Meng, Yu, Dejie, Chai, Bing Han, Tan, Bobby, Tsang, Fai, Tai, Yee Kit, Tan, Bryce Wei Quan, Liang, Mui Cheng, Tan, Hwee Tong, Tang, Jia Ying, Lai, Mitchell Kim Peng, Chua, John Jia En, Chung, Maxey Ching Ming, Khanna, Sanjay, Lim, Kah-Leong, Soong, Tuck Wah (2018-09-26). S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit. JOURNAL OF NEUROSCIENCE 38 (39) : 8364-8377. ScholarBank@NUS Repository. https://doi.org/10.1523/JNEUROSCI.3262-17.2018
Abstract: © 2018 the authors. Elevated iron deposition has been reported in Parkinson’s disease (PD). However, the route of iron uptake leading to high deposition in the substantia nigra is unresolved. Here, we show a mechanism in enhanced Fe 2+ uptake via S-nitrosylation of divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, in human PD brains, endogenously S-nitrosylated DMT1 was detected in postmortem substantia nigra. Patch-clamp electrophysiological recordings and iron uptake assays confirmed increased Mn 2+ or Fe 2+ 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 nitric oxide (NO)-mediated DMT1 current increase. To evaluate in vivo significance, lipopolysaccharide (LPS) was stereotaxically injected into the substantia nigra of female and male mice to induce inflammation and production of NO. The intranigral LPS injection resulted in corresponding increase in Fe 2+ deposition, JNK activation, dopaminergic neuronal loss and deficit in motoric activity, and these were rescued by the NO synthase inhibitor L -NAME or by the DMT1-selective blocker ebselen. Lentiviral knockdown of DMT1 abolished LPS-induced dopaminergic neuron loss.
Source Title: JOURNAL OF NEUROSCIENCE
URI: https://scholarbank.nus.edu.sg/handle/10635/155076
ISSN: 0270-6474
1529-2401
DOI: 10.1523/JNEUROSCI.3262-17.2018
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