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首页> 外文期刊>Cell discovery. >Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice
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Manganese transporter Slc39a14 deficiency revealed its key role in maintaining manganese homeostasis in mice

机译：锰转运蛋白Slc39a14缺乏症揭示了其在维持小鼠体内锰稳态中的关键作用

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SLC39A14 (also known as ZIP14), a member of the SLC39A transmembrane metal transporter family, has been reported to mediate the cellular uptake of iron and zinc. Recently, however, mutations in the SLC39A14 gene have been linked to manganese (Mn) accumulation in the brain and childhood-onset parkinsonism dystonia. It has therefore been suggested that SLC39A14 deficiency impairs hepatic Mn uptake and biliary excretion, resulting in the accumulation of Mn in the circulation and brain. To test this hypothesis, we generated and characterized global Slc39a14 -knockout ( Slc39a14 ?/? ) mice and hepatocyte-specific Slc39a14 -knockout ( Slc39a14 fl/fl ;Alb-Cre + ) mice. Slc39a14 ?/? mice develop markedly increased Mn concentrations in the brain and several extrahepatic tissues, as well as motor deficits that can be rescued by treatment with the metal chelator Na2CaEDTA. In contrast, Slc39a14 fl/fl ;Alb-Cre + mice do not accumulate Mn in the brain or other extrahepatic tissues and do not develop motor deficits, indicating that the loss of Slc39a14 expression selectively in hepatocytes is not sufficient to cause Mn accumulation. Interestingly, Slc39a14 fl/fl ;Alb-Cre + mice fed a high Mn diet have increased Mn levels in the serum, brain and pancreas, but not in the liver. Taken together, our results indicate that Slc39a14 ?/? mice develop brain Mn accumulation and motor deficits that cannot be explained by a loss of Slc39a14 expression in hepatocytes. These findings provide insight into the physiological role that SLC39A14 has in maintaining Mn homeostasis. Our tissue-specific Slc39a14 -knockout mouse model can serve as a valuable tool for further dissecting the organ-specific role of SLC39A14 in regulating the body’s susceptibility to Mn toxicity.
机译：SLC39A14（也称为ZIP14）是SLC39A跨膜金属转运蛋白家族的成员，据报道可介导细胞对铁和锌的吸收。然而，最近，SLC39A14基因的突变与大脑中锰（Mn）的积累和儿童期帕金森氏肌张力障碍有关。因此，已经提出SLC39A14缺乏会损害肝中Mn的摄取和胆汁排泄，从而导致Mn在循环系统和大脑中的积累。为了验证该假设，我们生成并表征了整体Slc39a14 -knockout（Slc39a14 ？/？）小鼠和肝细胞特异性Slc39a14 -knockout（Slc39a14 fl / fl ; Alb-Cre + ）小鼠。 Slc39a14 ？/？ 小鼠的大脑和一些肝外组织中的锰浓度显着升高，并且运动缺陷可以通过金属螯合剂Na 2 CaEDTA处理而得以挽救。相反，Slc39a14 fl / fl ; Alb-Cre + 小鼠在大脑或其他肝外组织中不积累Mn，也不产生运动功能障碍，这表明Slc39a14在肝细胞中选择性表达不足以引起Mn积累。有趣的是，饲喂高锰饮食的Slc39a14 fl / fl ; Alb-Cre + 小鼠的血清，脑和胰腺中的Mn水平升高，但肝脏中的Mn水平升高。两者合计，我们的结果表明Slc39a14 ？/？ 小鼠出现脑锰积累和运动功能障碍，这不能用肝细胞中Slc39a14表达的丧失来解释。这些发现提供了对SLC39A14在维持Mn稳态中的生理作用的见解。我们的组织特异性Slc39a14敲除小鼠模型可以作为有价值的工具，进一步剖析SLC39A14在调节机体对Mn毒性敏感性中的器官特异性作用。

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