Zinc Transporters ZnT3 and ZnT6 Are Downregulated in the Spinal Cords of Patients With Sporadic Amyotrophic Lateral Sclerosis

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. (c) 2014 Wiley Periodicals, Inc.

必需金属内稳态的失衡与多种疾病相关，包括神经退行性疾病。先前的研究表明，肌萎缩侧索硬化（ALS）患者的脑脊液中锌（Zn）水平显著升高。锌转运蛋白和金属硫蛋白紧密控制细胞内和细胞外的锌水平。本研究调查了ALS患者和模型小鼠中锌转运蛋白家族ZnT的蛋白质水平。评估了人类对照受试者脊髓中ZnT1、-3、-4、-5、-6、-7和-10的mRNA表达。与对照组相比，散发性ALS患者脊髓中ZnT3和ZnT6的蛋白质水平显著降低。此外，免疫组织化学染色显示ALS患者脊髓腹角中ZnT3和ZnT6的免疫反应性降低。而且，免疫组织化学分析表明，脊髓中表达的所有ZnT都定位于运动神经元的一个特定亚群。此外，与对照组相比，在出现ALS症状之前或之后，SOD1（G93A）突变转基因小鼠中ZnT3和ZnT6的蛋白质水平没有改变。这些结果表明，散发性ALS患者脊髓中ZnT3和ZnT6的蛋白质水平降低；然而，这并非仅仅由于运动神经元的缺失所致。（c）2014威利期刊公司