Zinc Transporter-3 Knockout Mice Demonstrate Age-Dependent Alterations in the Metalloproteome

Abstract

Metals are critical cellular elements that are involved in a variety of cellular processes, with recent literature demonstrating that zinc, and the synaptic zinc transporter (ZnT3), are specifically involved in learning and memory and may also be key players in age-related neurodegenerative disorders such as Alzheimer’s disease. Whilst the cellular content and location of metals is critical, recent data has demonstrated that the metalation state of proteins is a determinant of protein function and potential toxicity. As we have previously reported that ZnT3 knockout (KO) mice have deficits in total zinc levels at both 3 and 6 months of age, we were interested in whether there might be changes in the metalloproteomic profile in these animals. To do this, we utilised size exclusion chromatography-inductively coupled plasma mass spectrometry (SEC-ICP-MS) and examined hippocampal homogenates from ZnT3 KO and age-matched wild-type mice at 3, 6 and 18 months of age. Our data suggest that there are alterations in specific metal binding proteins, for zinc, copper and iron all being modulated in the ZnT3 KO mice compared to wild-type (WT). These data suggest that ZnT3 KO mice may have impairments in the levels or localisation of multiple transition metals, and that copper- and iron-dependent cellular pathways may also be impacted in these mice.

Recent Advances in Metalloproteomics

“…All three metals were increased in the disease model mice compared to wild-type controls, and their speciation was also altered, with a trend towards less protein-bound metal. A study by the same team of labs using the same approach found that mice that lack the zinc transporter ZnT-3 had altered speciation for not only Zn, but also Fe and Cu [138].…”

Zinc in the Brain: Friend or Foe?

“…ZnT3 knockout mice are deficient in total zinc concentrations at both three and six months. ZnT3 is known to be heavily involved in learning and memory and also to play a major role in aging-related neurodegenerative diseases [ 69 ]. Our laboratory has demonstrated that synaptic zinc is an important factor for modulating hippocampal neurogenesis, and we used ZnT3 knockout mice to address this question.…”

Distribution of Copper, Iron, and Zinc in the Retina, Hippocampus, and Cortex of the Transgenic APP/PS1 Mouse Model of Alzheimer’s Disease

“…Interestingly, our results demonstrate lower Zn levels in the retina, hippocampus, and cortex of APP/PS1 compared with WT mice. A likely explanation for our finding is based on the fact that previous studies have shown that Zinc Transporter 3 (ZnT3) proteins are essential for loading Zn into synaptic vessels [ 89 , 90 , 91 ]. These proteins are abundantly available during the early stages of AD and its only with ageing that ZnT3 levels are depleted resulting in higher levels of free Zn.…”