Disordered iron regulation in manganese Parkinsonism: Roles of divalent metal transporter 1, metal transporter protein 1 and transferrin receptor in the blood-CSF barrier

Xueqian Wang, Purdue University

Abstract

Overexposure to manganese (Mn) is believed to be one of the environmental factors that causes neurological symptoms resembling Parkinson's disease, referred to as manganism. For a chemical to induce brain dysfunction, it must pass across brain barriers. The barrier that restricts substance movement between the blood circulation and the cerebrospinal fluid (CSF) is termed the blood-CSF barrier (BCB), which primarily resides in the choroid plexus (CP). Previous studies have demonstrated that Mn exposure, decreases iron (Fe) levels in the blood and increases Fe concentrations in the CSF. This indicates a compartmental shift of Fe between the blood and CSF. Fe homeostasis is regulated by three major Fe transporters, i.e., divalent metal transporter 1 (DMT1), metal transporter protein 1 (MTP1), and transferrin receptor (TfR). We hypothesized that Mn exposure alters the expression, subcellular location, and function of DMT1, MTP1 and TfR at the BCB in the CP, which contributes to disordered Fe homeostasis in Mn-induced Parkinsonism. This project (i) demonstrated that Mn exposure increased the expression of OMT1 in the CP at both mRNA and protein levels as a result of increased binding between the IRE-containing DMT1 mRNA and the iron regulatory proteins, (ii) characterized the subcellular location of DMT1, MTP1 and TfR in the CP by confocal microscopy and identified that Mn/Fe exposure from the CSF caused intracellular trafficking of MTP1 and TfR, (iii) found that MTP1 dissociated from endoplasmic reticulum following Mn exposure in the choroidal epithelial Z310 cells as determined by use of GFP-tagged proteins and DMT1 was cytosolically localized, (iv) identified that transferrin-bound Fe favored influx from the blood to the CSF through the use of a bicameral Transwell device, while Mn exposure greatly increased free Fe transport favored in the opposite direction, and (v) discovered a lower Fe clearance in the CSF of Mn-treated rats by a ventriculocisternal brain perfusion technique. Overall, we conclude that Mn exposure alters the expression and subcellular location of these metal transporters (DMT1, MTP1 and TfR) in the BCB, leading to an increased Fe level in the CSF. It is concluded that these changes underlie Mn-elicited Parkinsonism.

Degree

Ph.D.

Advisors

Zheng, Purdue University.

Subject Area

Neurosciences|Toxicology

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