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 fluid, or blood, and
whether and how Mn exposure affects the transport function of both
Cu-ATPases, remained unanswered. This study was designed to characterize
the role of Cu-ATPases in regulating Cu transport at the blood-brain and
blood-cerebrospinal fluid barriers and to investigate how exposure to Mn
may alter the function of ATP7A and ATP7B, thereby contributing to the
etiology of Mn-induced Parkinsonian disorder.