Manganese transport, homeostasis, and neurotoxicity

Manganese (Mn) is an essential metal required for many physiological functions, and deficiency or over-exposure is associated with neurological dysfunction and neuropathology. Tight homeostatic control of Mn in the body is required to maintain optimal physiological levels and protect against toxicity. Mn homeostasis has been studied for decades, but there has been limited knowledge of the molecular mechanisms until recently, when the first human genetic disorders of Mn metabolism were described. These discoveries led to the identification of the Mn transporters SLC30A10, SLC39A14, and SLC39A8, which spurred a transformation of research into Mn homeostatic mechanisms. This review will provide an overview of Mn physiology and homeostasis, the role of the critical Mn transporters, and discuss the progress made within recent years towards understanding how these transporters work together to regulate brain Mn biology under both physiological and pathophysiological Mn conditions.