Zinc transporters ZnT3 and ZnT6 are downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis

Abstract

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons.

Zinc Transporter 3 (Znt3) as an Active Substance in the Enteric Nervous System of the Porcine Esophagus

“…Moreover, ZnT3 is known as substance characteristic of inhibitory zinc-enriched nerves (Wang et al 2002). Other studies showed that this substance is also involved in pathological processes concerning the central nervous system (Takeda 2000; Molnar and Nadler 2001; Kaneko et al 2015). Since there is a high degree of co-localization of zinc transporter 3 with active zinc in the same neurons of central and peripheral nervous system, ZnT3 is considered to be a substance typical for neuronal cells, which use zinc as the neuromodulator (Wang et al 2003).…”

“…ZnT3 has been described in different regions of the central and peripheral nervous system (Wenzel et al 1997; Wang et al 2002, 2005; Kaneko et al 2015). First of all, Znt3 is considered to be a marker of zinc-enriched (ZEN) terminals within brain, spinal cord, and superior cervical ganglion (Jo et al 2000; Wenzel et al 1997).…”

“…First of all, Znt3 is considered to be a marker of zinc-enriched (ZEN) terminals within brain, spinal cord, and superior cervical ganglion (Jo et al 2000; Wenzel et al 1997). These nerves, and indeed ZnT3, show inhibitory effects and take part in sensory conduction and excretive function, as well as play some, not fully explained, roles during pathological processes, such as epilepsy, cerebral ischemia, and amyotrophic lateral sclerosis (Takeda 2000; Danscher et al 2001; Molnar and Nadler 2001; Kaneko et al 2015). …”

Zinc Transporter 3 (ZnT3) in the Enteric Nervous System of the Porcine Ileum in Physiological Conditions and during Experimental Inflammation

“…From among the ZnT family of zinc transporters, only ZnT3 is closely linked to neuronal cells, where it is responsible for transport of zinc ions from the cytoplasm to synaptic vesicles, and thereby may influence neuronal conduction [12]. ZnT3 has been described in the brain, spinal cord and autonomic peripheral nervous system [13,14,15]. Within the central nervous system, this protein may be responsible for both sensory conduction and secretory activity and is also considered to be a marker of zinc-enriched nerves (ZEN), which have an inhibitory function [16].…”

Analysis of Zinc-Exporters Expression in Prostate Cancer

“…SLC30A6 expression has been implicated in Alzheimer’s disease and is overexpressed in the hippocampus/parahippocampal gyrus and cerebellum of pre-clinical Alzheimer’s disease subjects43. However, SLC30A6 is downregulated in the spinal cords of patients with sporadic amyotrophic lateral sclerosis44. SLC30A6 is expressed uniformly across the prostate lobes during sexual maturation in mice45.…”