Upregulation of zinc transporter 2 in the blood–CSF barrier following lead exposure

Abstract

Zinc (Zn) is an essential element for normal brain function; an abnormal Zn homeostasis in brain and the cerebrospinal fluid (CSF) has been implied in the etiology of Alzheimer’s disease (AD). However, the mechanisms that regulate Zn transport in the blood–brain interface remain unknown. This study was designed to investigate Zn transport by the blood–CSF barrier (BCB) in the choroid plexus, with a particular focus on Zn transporter-2 (ZnT2), and to understand if lead (Pb) accumulation in the choroid plexus disturbed the Zn regulatory function in the BCB. Confocal microscopy, quantitative PCR and western blot demonstrated the presence of ZnT2 in the choroidal epithelia; ZnT2 was primarily in cytosol in freshly isolated plexus tissues but more toward the peripheral membrane in established choroidal Z310 cells. Exposure of rats to Pb (single ip injection of 50mg Pb acetate/kg) for 24 h increased ZnT2 fluorescent signals in plexus tissues by confocal imaging and protein expression by western blot. Similar results were obtained by in vitro experiments using Z310 cells. Further studies using cultured cells and a two-chamber Transwell device showed that Pb treatment significantly reduced the cellular Zn concentration and led to an increased transport of Zn across the BCB, the effect that may be due to the increased ZnT2 by Pb exposure. Taken together, these results indicate that ZnT2 is present in the BCB; Pb exposure increases the ZnT2 expression in choroidal epithelial cells by a yet unknown mechanism and as a result, more Zn ions may be deposited into the intracellular Zn pool, leading to a relative Zn deficiency state in the cytoplasm at the BCB.

Exome Sequencing of SLC30A2 Identifies Novel Loss- and Gain-of-Function Variants Associated with Breast Cell Dysfunction

“…The zinc (Zn) transporter ZnT2 (SLC30A2) is a member of the SLC30A (solute carrier family 30A) family and is highly expressed in specialized secretory epithelial cells including prostate [1], acinar pancreas [2], choroid [3] and mammary gland [4]. ZnT2 contains six transmembrane domains with cytoplasmic N-and C-termini, and functions as a dimer [5] to import Zn into mitochondria [6] and vesicles [7] in mammary epithelial cells (MECs).…”

TNFα Post‐Translationally Targets ZnT2 to Accumulate Zinc in Lysosomes

“…This is consistent with our findings in that a physiological stressor enhanced the binding of AP‐3 and retargeted ZnT2 to lysosomes and suggests that other secretory tissues, such as the prostate and pancreatic β‐cells, may respond to exogenous cues in a similar manner. Moreover, ZnT2 is also highly expressed in the prostate (Iguchi et al, ), acinar pancreas (Guo et al, ), and choroid plexus (Fu et al, ), which all undergo LCD during pathogenesis (Zeligs et al, ; Nixon and Cataldo, ; Sinha et al, ). For example, LCD occurs in all forms of neurodegeneration (Nixon and Cataldo, ) and Zn accumulation in lysosomes causes LMP and induces neuronal and astrocyte cell death (Hwang et al, ; Lee et al, , Park et al, ).…”

High proportion of transient neonatal zinc deficiency causing alleles in the general population

“…Based on this information and on the cases that were published in the literature in women harbouring inactivating ZnT2 mutations, we considered these women healthy individuals. ZnT2 expression was demonstrated in rat and mouse tissues or cultured cell lines . Regarding the expression of ZnT2 in human cells, Leung et al, were the first to show that ZnT2 mRNA levels were readily detected in human retinal ARPE19 cells and in primary foetal RPE cells but not in adult retinal pigment epithelial cells.…”

“…ZnT2 expression was demonstrated in rat and mouse tissues or cultured cell lines. [26][27][28][29][30][31][32][33] Regarding the expression of ZnT2 in human cells, Leung et al, 34 were the first to show that ZnT2 mRNA levels were readily detected in human retinal ARPE19 cells and in primary foetal RPE cells but not in adult retinal pigment epithelial cells. We have previously shown the expression of ZnT2 in cells freshly isolated from human breast milk samples (Golan et al 20 ).…”