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首页> 外文期刊>PLoS Genetics >Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis
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Zebrafish slc30a10 deficiency revealed a novel compensatory mechanism of Atp2c1 in maintaining manganese homeostasis

机译：斑马鱼SLC30A10缺乏揭示了ATP2C1在维持锰稳态的新型补偿机制

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Recent studies found that mutations in the human SLC30A10 gene, which encodes a manganese (Mn) efflux transporter, are associated with hypermanganesemia with dystonia, polycythemia, and cirrhosis (HMDPC). However, the relationship between Mn metabolism and HMDPC is poorly understood, and no specific treatments are available for this disorder. Here, we generated two zebrafish slc30a10 mutant lines using the CRISPR/Cas9 system. Compared to wild-type animals, mutant adult animals developed significantly higher systemic Mn levels, and Mn accumulated in the brain and liver of mutant embryos in response to exogenous Mn. Interestingly, slc30a10 mutants developed neurological deficits in adulthood, as well as environmental Mn-induced manganism in the embryonic stage; moreover, mutant animals had impaired dopaminergic and GABAergic signaling. Finally, mutant animals developed steatosis, liver fibrosis, and polycythemia accompanied by increased epo expression. This phenotype was rescued partially by EDTA- CaNa2 chelation therapy and iron supplementation. Interestingly, prior to the onset of slc30a10 expression, expressing ATP2C1 (ATPase secretory pathway Ca2+ transporting 1) protected mutant embryos from Mn exposure, suggesting a compensatory role for Atp2c1 in the absence of Slc30a10. Notably, expressing either wild-type or mutant forms of SLC30A10 was sufficient to inhibit the effect of ATP2C1 in response to Mn challenge in both zebrafish embryos and HeLa cells. These findings suggest that either activating ATP2C1 or restoring the Mn-induced trafficking of ATP2C1 can reduce Mn accumulation, providing a possible target for treating HMDPC.
机译：最近的研究发现，人SLC30A10基因中的突变编码锰（MN）流出转运蛋白，与具有肌肌瘤，多胆血症和肝硬化（HMDPC）的高锰血症相关。然而，Mn代谢与HMDPC之间的关系理解得很差，并且该疾病没有任何特异性处理。在这里，我们使用CRISPR / CAS9系统生成了两个斑马鱼SLC30A10突变线。与野生型动物相比，突变体成年动物的全身MN水平显着较高，响应于外源Mn的突变胚胎的脑和肝脏中累积的Mn。有趣的是，SLC30A10突变体在成年期开发了神经学缺陷，以及在胚胎阶段的环境MN诱导的甘锰;此外，突变动物已经受到多巴胺能和胃肠杆菌信号传导的损害。最后，突变动物产生了脂肪变性，肝纤维化和多胆血症，伴随着增加的EPO表达。该表型部分通过EDTA-CANA2螯合疗法和铁补充来拯救。有趣的是，在SLC30A10表达的发作之前，表达ATP2C1（ATP酶分泌途径CA2 +传输1）受到Mn暴露的保护突变体胚胎，表明在没有SLC30A10的情况下对ATP2C1的补偿作用。值得注意的是，表达野生型或突变形式的SLC30A10足以抑制ATP2C1响应于斑马鱼胚和HELA细胞中的MN攻击的效果。这些发现表明，激活ATP2C1或恢复MN诱导的ATP2C1的运输可以减少Mn累积，提供用于治疗HMDPC的可能靶标。

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