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.

SIGNIFICANCE STATEMENT Manganese is an essential micronutrient. When acquired in excess, manganese accumulates in tissues of the CNS and is associated with neurodegenerative disease, particularly Parkinson-like syndrome and dystonia. Some members of the ZIP metal transporter family transport manganese. Using mutant mice deficient in the ZIP14 metal transporter, we have discovered that ZIP14 is essential for manganese elimination via the gastrointestinal tract, and a lack of ZIP14 results in manganese accumulation in critical tissues such as the brain, as measured by MRI, and produces signatures of brain injury and impaired motor function. Humans with altered ZIP14 function would lack this gatekeeper function of ZIP14 and therefore would be prone to manganese-related neurological diseases.