Altered brain copper (Cu) homeostasis has been associated with idiopathic Parkinson's disease (IPD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and Prion disease. We have recently discovered that Cu levels in blood and saliva of Mn-exposed workers from human cohorts are significantly increased, and so are the Cu levels in the CSF and brain tissues of Mn- exposed animals. While the presence of transporters possibly responsible for Cu transport in brain barriers such as Cu transport protein-1 (Ctr1), divalent metal transporter-1 (DMT1) and ATP7A has been demonstrated, how Cu is transported by these transporters in brain barriers and by what mechanism exposure to manganese (Mn) alters the expression and function of these transporters are unknown. This research project is designed to test the hypothesis that the choroid plexus, a brain tissue forming a barrier between the blood and cerebrospinal fluid (CSF), regulates Cu transport between the blood and CSF through the critical transporters;exposure to Mn alters the functions of these transporters, leading to a distorted Cu homeostasis in the CSF. To test this hypothesis, we have designed 4 specific aims.
In Aim 1, we will determine if subchronic exposure to Mn in a rat model alters the expression of Ctr1, DMT1 and ATP7A in blood-brain barrier (BBB) and blood-CSF barrier (BCB), leading to an increased influx of Cu from the blood to brain parenchyma and a decreased Cu efflux from the CSF to blood.
In Aim 2, we will reveal if Ctr1 and DMT1 coordinate the Cu uptake on the surface of the BBB and BCB and if Mn exposure disrupts these processes, leading to cellular overload of Cu by the brain barrier cells.
Aim 3 is designed to investigate if the intracellular trafficking of ATP7A determines the direction of Cu transport by the BCB and if Mn exposure, by acting on ATP7A, may alter the direction of Cu transport between the blood and the CSF. Finally, in Aim 4, we will use the synchrotron rapid scanning X-ray fluorescence (RS-XRF) technique, by collaboration with the professor in Purdue's Physics department, to establish 3D model to simultaneously localize and quantify Cu, Fe, Mn and Zn in brains of Mn-exposed rats. The studies proposed in this application will define the inter-relationship between Ctr1, DMT1 and ATP7A in brain barriers with regard to their subcellular locations, roles in transport of Cu, and their regulation as affected by Mn exposure;will provide the insight into the molecular mechanism by which Mn affects Cu transport by brain barriers;and will ultimately provide a better understanding of Cu dysregulation-related neurodegenerative diseases.

Public Health Relevance

Altered brain copper (Cu) homeostasis has been associated with idiopathic Parkinson's disease (IPD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and Prion disease. This project will uncover how Cu is transferred in and out of the brain and how exposure to environmental toxicant manganese (Mn) interferes with the Cu balance in brain, which in turn causes the degenerative manganese parkinsonism.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES008146-16
Application #
8435445
Study Section
Special Emphasis Panel (ZRG1-IFCN-A (03))
Program Officer
Lawler, Cindy P
Project Start
1998-03-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
16
Fiscal Year
2013
Total Cost
$329,040
Indirect Cost
$108,772
Name
Purdue University
Department
Other Health Professions
Type
Schools of Public Health
DUNS #
072051394
City
West Lafayette
State
IN
Country
United States
Zip Code
47907
Fu, Sherleen; Jiang, Wendy; Gao, Xiang et al. (2016) Aberrant Adult Neurogenesis in the Subventricular Zone-Rostral Migratory Stream-Olfactory Bulb System Following Subchronic Manganese Exposure. Toxicol Sci 150:347-68
Fu, Sherleen; O'Neal, Stefanie; Hong, Lan et al. (2015) Elevated adult neurogenesis in brain subventricular zone following in vivo manganese exposure: roles of copper and DMT1. Toxicol Sci 143:482-98
O'Neal, Stefanie L; Zheng, Wei (2015) Manganese Toxicity Upon Overexposure: a Decade in Review. Curr Environ Health Rep 2:315-28
Gu, H; Zhong, Z; Jiang, W et al. (2014) The role of choroid plexus in IVIG-induced beta-amyloid clearance. Neuroscience 270:168-76
O'Neal, Stefanie L; Lee, Jang-Won; Zheng, Wei et al. (2014) Subacute manganese exposure in rats is a neurochemical model of early manganese toxicity. Neurotoxicology 44:303-13
Fu, Xue; Zhang, Yanshu; Jiang, Wendy et al. (2014) Regulation of copper transport crossing brain barrier systems by Cu-ATPases: effect of manganese exposure. Toxicol Sci 139:432-51
Hong, Lan; Xu, Cong; O'Neal, Stefanie et al. (2014) Roles of P-glycoprotein and multidrug resistance protein in transporting para-aminosalicylic acid and its N-acetylated metabolite in mice brain. Acta Pharmacol Sin 35:1577-85
Fu, Xue; Zeng, Andrew; Zheng, Wei et al. (2014) Upregulation of zinc transporter 2 in the blood-CSF barrier following lead exposure. Exp Biol Med (Maywood) 239:202-12
Zheng, Gang; Zhang, Jieqiong; Xu, Yan et al. (2014) Involvement of CTR1 and ATP7A in lead (Pb)-induced copper (Cu) accumulation in choroidal epithelial cells. Toxicol Lett 225:110-8
Liu, Yingzi; Byrne, Patrick; Wang, Haoyu et al. (2014) A compact DD neutron generator-based NAA system to quantify manganese (Mn) in bone in vivo. Physiol Meas 35:1899-911

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