Protective function of SLC30A10 induced via PERK-ATF4 pathway against 1-methyl-4-phenylpyridinium

Abstract

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-phenyl-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 MPP+ 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.