期刊
JOURNAL OF NEUROSCIENCE
卷 37, 期 25, 页码 5996-6006出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0285-17.2017
关键词
dystonia; neurodegeneration; neuroinflammation; Parkinson's; transport; zinc
资金
- National Institute of Diabetes and Digestive and Kidney Diseases [5R01-DK-094244]
- Boston Family Endowment Funds of the University of Florida
- National High Magnetic Field Laboratory Advanced Magnetic Resonance Imaging and Spectroscopy Facility (National Science Foundation) [DMR-1157490]
- National High Magnetic Field Laboratory Advanced Magnetic Resonance Imaging and Spectroscopy Facility (State of Florida)
Mutations in human ZIP14 have been linked to symptoms of the early onset of Parkinsonism and Dystonia. This phenotype is likely related to excess manganese accumulation in the CNS. The metal transporter ZIP14 (SLC39A14) is viewed primarily as a zinc transporter that is inducible via proinflammatory stimuli. In vitro evidence shows that ZIP14 can also transport manganese. To examine a role for ZIP14 in manganese homeostasis, we used Zip14 knock-out (KO) male and female mice to conduct comparative metabolic, imaging, and functional studies. Manganese accumulation was fourfold to fivefold higher in brains of Zip14 KO mice compared with young adult wild-type mice. There was less accumulation of subcutaneously administered Mn-54 in the liver, gallbladder, and gastrointestinal tract of the KO mice, suggesting that manganese elimination is impaired with Zip14 ablation. Impaired elimination creates the opportunity for atypical manganese accumulation in tissues, including the brain. The intensity of MR images from brains of the Zip14 KO mice is indicative of major manganese accumulation. In agreement with excessive manganese accumulation was the impaired motor function observed in the Zip14 KO mice. These results also demonstrate that ZIP14 is not essential for manganese uptake by the brain. Nevertheless, the upregulation of signatures of brain injury observed in the Zip14KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.
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