Metal transporter Zip14 (Slc39a14) deletion in mice increases manganese deposition and produces neurotoxic signatures and diminished motor activity

Tolunay Beker Aydemir, Min Hyun Kim, Jinhee Kim, Luis M. Colon-Perez, Guita Banan, Thomas H. Mareci, Marcelo Febo, Robert J. Cousins

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

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 54Mn 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 Zip14 KO mice demonstrates that normal ZIP14 function is an essential factor required to prevent manganese-linked neurodegeneration.

Original languageEnglish
Pages (from-to)5996-6006
Number of pages11
JournalJournal of Neuroscience
Volume37
Issue number25
DOIs
StatePublished - 21 Jun 2017

Keywords

  • Dystonia
  • Neurodegeneration
  • Neuroinflammation
  • Parkinson’s
  • Transport
  • Zinc

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