Disordered copper transport across the brain barrier systems following manganese exposure: The role of copper transporters ATP7A and ATP7B

Xue Fu, Purdue University

Abstract

Increased copper (Cu) levels in blood, saliva and brain are found in manganese (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 a dual role in either delivering Cu ions into the Golgi lumen for the biosynthesis of Cu-depending enzymes (secretory pathway) under the basal Cu level, or expelling excessive Cu from the cytosol into the extracellular space when the Cu level exceeds the baseline. However, the questions as to whether and how these Cu-ATPases in the brain barrier systems transport Cu, i.e., toward brain parenchyma, cerebrospinal fluid (CSF), or blood, and whether and how Mn exposure affects the transport function of ATP7A and ATP7B, remained unanswered. This study was designed to characterize the role of Cu-ATPases in regulating Cu transport at the blood-brain barrier (BBB) and blood-CSF barrier (BCB) and to investigate how exposure to toxic metal Mn may alter the function of Cu-ATPases, thereby contributing to the etiology of Mn-induced Parkinsonian disorder. This project clearly indicated that: (i) Mn exposure significantly increased Mn and Cu concentrations in selected brain regions, serum, CSF and choroid plexus tissues; (ii) the BBB appeared to be a major site for Cu entry into the brain, whereas the BCB served as the predominant route for Cu efflux from the CSF to the blood; (iii) Mn exposure interrupted the Cu transport across the BBB and BCB by increasing the Cu uptake via the BBB and diminishing the Cu efflux through the BCB; (iv) both ATP7A and ATP7B were abundantly expressed in the BBB and BCB; (v) when excess Mn or Cu present in choroidal epithelia, ATP7A relocated toward the apical microvilli surface to export Cu into the CSF, while ATP7B redistributed toward the basolateral membrane to eliminate Cu into the blood circulation; and (vi) Mn exposure, by inhibiting the production and function of ATP7A and ATP7B, increased the intracellular Cu retention and reduced the efflux transport of Cu from the CSF to the blood in the BBB and BCB in vitro models. Overall, we conclude that Mn exposure seems likely to disrupt the Cu transport across both barrier systems mainly by interaction with ATP7A and ATP7B.

Degree

Ph.D.

Advisors

Zheng, Purdue University.

Subject Area

Toxicology|Surgery|Health sciences

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