Please use this identifier to cite or link to this item: https://doi.org/10.1523/JNEUROSCI.3262-17.2018
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dc.titleS-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit
dc.contributor.authorLiu, Chao
dc.contributor.authorZhang, Cheng-Wu
dc.contributor.authorLo, Shun Qiang
dc.contributor.authorAng, Seok Ting
dc.contributor.authorChew, Katherine Chee Meng
dc.contributor.authorYu, Dejie
dc.contributor.authorChai, Bing Han
dc.contributor.authorTan, Bobby
dc.contributor.authorTsang, Fai
dc.contributor.authorTai, Yee Kit
dc.contributor.authorTan, Bryce Wei Quan
dc.contributor.authorLiang, Mui Cheng
dc.contributor.authorTan, Hwee Tong
dc.contributor.authorTang, Jia Ying
dc.contributor.authorLai, Mitchell Kim Peng
dc.contributor.authorChua, John Jia En
dc.contributor.authorChung, Maxey Ching Ming
dc.contributor.authorKhanna, Sanjay
dc.contributor.authorLim, Kah-Leong
dc.contributor.authorSoong, Tuck Wah
dc.date.accessioned2019-06-03T05:00:48Z
dc.date.available2019-06-03T05:00:48Z
dc.date.issued2018-09-26
dc.identifier.citationLiu, 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
dc.identifier.issn0270-6474
dc.identifier.issn1529-2401
dc.identifier.urihttps://scholarbank.nus.edu.sg/handle/10635/155076
dc.description.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.
dc.language.isoen
dc.publisherSOC NEUROSCIENCE
dc.sourceElements
dc.subjectScience & Technology
dc.subjectLife Sciences & Biomedicine
dc.subjectNeurosciences
dc.subjectNeurosciences & Neurology
dc.subjectDMT1
dc.subjectdopaminergic neurons
dc.subjectiron deposition
dc.subjectmotoric defects
dc.subjectnitric oxide
dc.subjectS-nitrosylation
dc.subjectRESIN-ASSISTED CAPTURE
dc.subjectNITRIC-OXIDE SYNTHASE
dc.subjectPARKINSONS-DISEASE
dc.subjectSUBSTANTIA-NIGRA
dc.subjectBINDING PROTEIN
dc.subjectUP-REGULATION
dc.subjectRAT-BRAIN
dc.subjectIN-VIVO
dc.subjectNEURODEGENERATION
dc.subjectMICROGLIA
dc.typeArticle
dc.date.updated2019-06-03T02:30:19Z
dc.contributor.departmentDEPT OF PHYSIOLOGY
dc.contributor.departmentDEPT OF CHEMISTRY
dc.contributor.departmentDEPT OF SURGERY
dc.contributor.departmentCENTRE FOR QUANTUM TECHNOLOGIES
dc.contributor.departmentDEPT OF BIOCHEMISTRY
dc.contributor.departmentDEPT OF PHARMACOLOGY
dc.description.doi10.1523/JNEUROSCI.3262-17.2018
dc.description.sourcetitleJOURNAL OF NEUROSCIENCE
dc.description.volume38
dc.description.issue39
dc.description.page8364-8377
dc.published.statePublished
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