UCL GOS Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, UK.
Dis Model Mech. 2022 Jun 1;15(6). doi: 10.1242/dmm.044594. Epub 2022 Jun 15.
Manganese neurotoxicity is a hallmark of hypermanganesemia with dystonia 2, an inherited manganese transporter defect caused by mutations in SLC39A14. To identify novel potential targets of manganese neurotoxicity, we performed transcriptome analysis of slc39a14-/- mutant zebrafish that were exposed to MnCl2. Differentially expressed genes mapped to the central nervous system and eye, and pathway analysis suggested that Ca2+ dyshomeostasis and activation of the unfolded protein response are key features of manganese neurotoxicity. Consistent with this interpretation, MnCl2 exposure led to decreased whole-animal Ca2+ levels, locomotor defects and changes in neuronal activity within the telencephalon and optic tectum. In accordance with reduced tectal activity, slc39a14-/- zebrafish showed changes in visual phototransduction gene expression, absence of visual background adaptation and a diminished optokinetic reflex. Finally, numerous differentially expressed genes in mutant larvae normalised upon MnCl2 treatment indicating that, in addition to neurotoxicity, manganese deficiency is present either subcellularly or in specific cells or tissues. Overall, we assembled a comprehensive set of genes that mediate manganese-systemic responses and found a highly correlated and modulated network associated with Ca2+ dyshomeostasis and cellular stress. This article has an associated First Person interview with the first author of the paper.
锰神经毒性是由 SLC39A14 基因突变引起的 dystonia 2 型高锰血症的标志，这是一种遗传性锰转运蛋白缺陷。为了确定锰神经毒性的新潜在靶点，我们对暴露于 MnCl2 的 slc39a14-/- 突变斑马鱼进行了转录组分析。差异表达的基因映射到中枢神经系统和眼睛，通路分析表明钙稳态失调和未折叠蛋白反应的激活是锰神经毒性的关键特征。与这一解释一致，MnCl2 暴露导致整个动物的钙水平降低、运动缺陷以及大脑和视顶盖内神经元活动的变化。与视顶盖活性降低一致，slc39a14-/- 斑马鱼表现出视觉光转导基因表达的变化、视觉背景适应的缺失和光运动反射的减弱。最后，在 MnCl2 处理后，突变幼虫中的许多差异表达基因正常化，这表明除了神经毒性外，锰缺乏还存在于亚细胞或特定细胞或组织中。总的来说，我们构建了一个综合的基因集合，这些基因介导了锰的全身反应，并发现了一个与钙稳态失调和细胞应激高度相关和调节的网络。本文有一篇与该论文第一作者的第一人称访谈。
