Increased Cu levels in blood, saliva and brain are found in Mn-exposed animals and humans; the underlying mechanism is unknown. Dyshomeostasis of Cu in the central nervous system is known to contribute to the pathogeneses of several neurodegenerative diseases. Regulation of cellular Cu homeostasis involves Cu-transporting ATPases (Cu-ATPases), i.e., ATP7A and ATP7b. Both transporters play an important role in removing excess Cu ions from the cytosol. However, the questions as to whether and how Cu-ATPases in the brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal...