Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish.
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SLC39A14的损失导致斑马鱼的同时锰超敏反应和缺乏。
DOI：
10.1242/dmm.044594
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发表时间：
2022-06-01
影响因子：
4.3
通讯作者：
中科院分区：
文献类型：
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作者：
锰神经毒性是高锰血症伴肌张力障碍 2 的一个标志，肌张力障碍 2 是一种由 SLC39A14 突变引起的遗传性锰转运蛋白缺陷。为了确定锰神经毒性的新潜在靶标，我们对暴露于 MnCl2 的 slc39a14−/− 突变斑马鱼进行了转录组分析。映射到中枢神经系统和眼睛的差异表达基因和通路分析表明，Ca2+ 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 Ca2+ 水平降低、运动缺陷以及端脑和视顶盖内神经元活动的变化。根据顶盖活动的减少，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视动反射的减弱。最后，突变幼虫中的许多差异表达基因在 MnCl2 处理后正常化，表明除了神经毒性之外，锰缺乏还存在于亚细胞或特定细胞或组织中。总体而言，我们组装了一套全面的介导锰系统反应的基因，并发现了与 Ca2+ 稳态失调和细胞应激相关的高度相关和调节的网络。摘要：斑马鱼 slc39a14−/− 突变体的转录组分析表明，slc39a14 的缺失会导致并发的锰神经毒性和缺乏，这两者都与 Ca2+ 体内平衡失调有关。
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. Summary: Transcriptome analysis of zebrafish slc39a14−/− mutants demonstrates that loss of slc39a14 leads to concurrent manganese neurotoxicity and deficiency, both of which are associated with Ca2+ dyshomeostasis.
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影响因子：
--
作者：
Caito, Samuel;Aschner, Michael
通讯作者：
Aschner, Michael
影响因子：
4.7
作者：
Hertz E;Terenius L;Vukojević V;Svenningsson P
通讯作者：
Svenningsson P
影响因子：
7.1
作者：
Jadiya P;Garbincius JF;Elrod JW
通讯作者：
Elrod JW
影响因子：
4.8
作者：
Hasegawa S;Kumagai M;Hagihara M;Nishimaru H;Hirano K;Kaneko R;Okayama A;Hirayama T;Sanbo M;Hirabayashi M;Watanabe M;Hirabayashi T;Yagi T
通讯作者：
Yagi T
影响因子：
4.4
作者：
Collins, John E.;Wali, Neha;Busch-Nentwich, Elisabeth M.
通讯作者：
Busch-Nentwich, Elisabeth M.