THE ROLE OF TRANSMEMBRANE 163 (Tmem163) PROTEIN IN TISSUE ZINC METABOLISM

Abstract

Human TMEM163 is a protein that has been reported to bind zinc, copper, and nickel. Our laboratory recently showed that TMEM163 transports zinc into intracellular compartments and out of cells, making it a zinc efflux transporter. TMEM163 has been implicated in several human disorders such as Mucolipidosis type IV, Hypomyelination Leukodystrophy, Parkinson’s disease and diabetes. We have previously shown that knocking down the expression of human TMEM163 in cultured cells creates an imbalance of intracellular zinc levels, suggesting that it is likely critical for zinc homeostasis in various cells and tissues. To further dissect the function of TMEM163, I used an animal model in which its mouse counterpart, Tmem163, has been knocked out. I hypothesized that with a loss of mouse Tmem163 expression will result in abnormal metabolism of metals, particularly those that were reported to bind Tmem163. I used post-mortem tissues from Tmem163 knockout (KO) and wildtype (WT) mice, consisting of cerebral cortex, cerebellum, lungs, and pancreas, because of prior knowledge that Tmem163 transcripts are highly expressed in these tissues. Using inductively coupled plasma mass spectrometry (ICP-MS), I analyzed the levels of metal isotopes of iron, nickel, copper, zinc, sodium, magnesium, calcium, and manganese from KO and WT tissues of 1-, 3-, 7- and 16-month-old mice. To corroborate with ICP-MS results, I used Timm Silver Sulfide to stain for hippocampal zinc from KO and WT tissues of 1-, 3-, 7-, and 12-month-old mice. Overall, these observations show that mouse Tmem163 is crucial for metal homeostasis in distinct tissues and zinc transport in the brain. Furthermore, these results suggest that human TMEM163 plays a vital roles in human health and disease