SLC39A14 deficiency alters manganese homeostasis and excretion resulting in brain manganese accumulation and motor deficits in mice

Significance Manganese (Mn) is an essential nutrient that is toxic in excess. Exposure to excess Mn can result in Mn accumulation in the brain and neurological and motor disturbances resembling Parkinson disease. Here, we demonstrate that the transmembrane metal-ion transporter solute carrier family 39, member 14 (SLC39A14) is essential for Mn homeostasis. We provide evidence that SLC39A14 is required for efficient Mn uptake by the liver and pancreas, two organs that are known to actively participate in Mn excretion from the body. Accordingly, loss of SLC39A14 impairs Mn excretion, leading to Mn accumulation in the brain and most other extrahepatic tissues. Slc39a14 -deficient mice, similar to SLC39A14 -deficient human patients, display motor deficits, and thus offer a convenient model to study Mn/SLC39A14-related neurotoxicity.