S-Nitrosylation of Divalent Metal Transporter 1 Enhances Iron Uptake to Mediate Loss of Dopaminergic Neurons and Motoric Deficit

• DOI: 10.1523/jneurosci.3262-17.2018
• Publication Date: 2018-08-13T17:47:55Z
• Authors: Chao Liu; Cheng-Wu Zhang; Shun Qiang Lo; Seok Ting Ang; Katherine Chee Me...; Dejie Yu; Bing Han Chai; Bobby Tan; Fai Tsang; Yee Kit Tai; Bryce Wei Quan Tan; Mui Cheng Liang; Hwee Tong Tan; Jia Ying Tang; Mitchell Kim Peng...; John Jia En Chua; Maxey Ching Ming ...; Sanjay Khanna; Kah-Leong Lim; Tuck Wah Soong
• Keywords: DMT1; S-Nitrosylation; Pars compacta; Nitrosylation

Elevated iron deposition has been reported in Parkinson's disease (PD). However, the route of uptake leading to high substantia nigra is unresolved. Here, we show a mechanism enhanced Fe 2+ via S-nitrosylation divalent metal transporter 1 (DMT1). While DMT1 could be S-nitrosylated by exogenous nitric oxide donors, human PD brains, endogenously was detected postmortem nigra. Patch-clamp electrophysiological recordings and assays confirmed increased Mn or through DMT1. We identified two major sites, C23 C540, mass spectrometry, C23A C540A substitutions abolished (NO)-mediated current increase. To evaluate vivo significance, lipopolysaccharide (LPS) stereotaxically injected into female male mice induce inflammation production NO. The intranigral LPS injection resulted corresponding increase deposition, JNK activation, dopaminergic neuronal loss deficit motoric activity, these were rescued NO synthase inhibitor l -NAME DMT1-selective blocker ebselen. Lentiviral knockdown LPS-induced neuron loss. SIGNIFICANCE STATEMENT Neuroinflammation cytoplasmic levels have implicated initiation progression neurodegenerative diseases. report unexpected enhancement functional activity transmembrane (DMT1) S-nitrosylation. demonstrated that DMT1-mediated uptake, cysteines spectrometry sites for uptake. One conceptual advance while external acidification because gating proton motive, discovered also Significantly, lipopolysaccharide-induced death ameliorated using -NAME, inhibitor, ebselen, blocker.