Protective function of SLC30A10 induced via PERK-ATF4 pathway against 1-methyl-4-phenylpyridinium
Protective function of SLC30A10 induced via PERK-ATF4 pathway against 1-methyl-4-phenylpyridinium
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DOI：
10.1016/j.bbrc.2017.07.018
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发表时间：
2017-09-02
影响因子：
3.1
通讯作者：
Hozumi, Isao
中科院分区：
文献类型：
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作者：
Go, Suzuna;Kurita, Hisaka;Hozumi, Isao
溶质载体家族30成员10（SLC 30 A10）被称为锰转运蛋白。研究表明，神经退行性疾病与细胞应激有关，如氧化应激或内质网（ER）应激。然而，SLC 30 A10是否真的参与了几种细胞内应激仍然是未知的。我们发现1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）处理的小鼠中脑中Slc 30 a10的水平增加。因此，我们进一步研究了SLC 30 A10在1-甲基-4-苯基吡啶离子（MPP+）诱导的细胞内应激中的作用，以及MIT+处理诱导SLC 30 A10的分子机制。在用MPP+（1 mM）处理的人神经母细胞瘤细胞系（SH-SY 5 Y）中，SLC 30 A10 mRNA水平显著增加，此外，MPP+显著增加了CHOP（已知为ER应激标志物之一）的表达。有趣的是，衣霉素作为ER应激物显著增加了SLC 30 A10 mRNA的水平，表明MPP+诱导SLC 30 A10是通过ER应激引起的。考虑到MPP+诱导的内质网应激可激活PKR样内质网激酶（PERK）通路，我们研究了PERK通路中的主要转录因子ATF 4是否能上调SLC 30 A10的表达。MPP+处理的细胞中SLC 30 A10表达的增加通过ATF 4敲低而消除。通过测定SLC 30 A10敲减细胞的细胞活力，证实了SLC 30 A10对MPP+诱导的ER应激的保护作用。总之，SLC 30 A10被认为通过PERK-ATF 4途径对MPP+诱导的毒性具有保护作用。(C)2017爱思唯尔公司All rights reserved.
Solute carrier family 30 member 10 (SLC30A10) has been known as manganese transporter. It has been suggested that neurodegenerative diseases are related with cellular stress such as oxidative stress or endoplasmic reticulum (ER) stress. However, it remains unknown whether SLC30A10 is actually involved in several intracellular stress. We found that the level of Slc30a10 was increased in midbrain of 1-methyl-4-pheny1-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Therefore, we further investigated the role of SLC30A10 in the 1-methyl-4-phenylpiridium ion (MPP+)-induced intracellular stress, and the molecular mechanism underlying SLC30A10 induction by MIT+ treatment. In human neuroblastoma cell line (SH-SY5Y) treated with MPP+ (1 mM), the SLC30A10 mRNA level was significantly increased, and in addition, the expression of CHOP, which is known as one of ER stress markers, was significantly increased by MPP+. Interestingly, the level of SLC30A10 mRNA was significantly increased by tunicamycin as an ER stressor, suggesting that the induction of SLC30A10 by MPP+ was caused via ER stress. Considering that PKR-like endoplasmic reticulum kinase (PERK) pathway is activated under ER stress induced by MPP+, we investigated whether the expression of SLC30A10 is increased through ATF4, which is major transcription factor in PERK pathway. The increase of SLC30A10 expression in MPP+-treated cells was eliminated by ATF4 knockdown. And the protective role of SLC30A10 against MPP+-induced ER stress was confirmed by measuring cell viability in SLC30A10 knockdown cells. In conclusion, SLC30A10 is thought to have protective role for MPP+-induced toxicity via PERK-ATF4 pathway. (C) 2017 Elsevier Inc. All rights reserved.