Journal
ENVIRONMENTAL TOXICOLOGY
Volume 33, Issue 3, Pages 315-324Publisher
WILEY
DOI: 10.1002/tox.22518
Keywords
alpha-synuclein oligomerization; autophagy; endoplasmic reticulum stress; manganese
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Funding
- National Natural Science Foundation of China [81773377]
- Liaoning Excellent Talents in University [LJQ2014089]
- Liaoning Innovative Research Team in University [LT2015028]
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Overexposure to manganese (Mn) has been known to induce alpha-synuclein (alpha-Syn) oligomerization, which is degraded mainly depending on endoplasmic reticulum stress (ER stress) and autophagy pathways. However, little data reported the cross-talk between ER stress and autophagy on Mn-induced alpha-Syn oligomerization. To explore the relationship between ER stress and autophagy, we used 4-phenylbutyric acid (4-PBA, the ER stress inhibitor), rapamycin (Rap, autophagy activator) and 3-methyladenine (3-MA, autophagy inhibitor) in mice model of manganism. After 4 weeks of treatment with Mn, both ER stress and autophagy were activated. Exposed to Mn also resulted in alpha-Syn oligomerization and neuronal cell damage in the brain tissue of mice, which could be relieved by 4-PBA pretreatment. Moreover, when the ER stress was inhibited, the activation of autophagy was also inhibited. Rap pretreatment significantly activated autophagy and decreased alpha-Syn oligomers. However, 3-MA pretreatment inhibited autophagy resulting in increase of alpha-Syn oligomers, and compensatorily activated PERK signaling pathway. Our results also demonstrated that the inhibition of autophagy by 3-MA aggravated neuronal cell damage. The findings clearly demonstrated that the cross-talking between autophagy and ER stress might play an important role in the alpha-Syn oligomerization and neurotoxicity by Mn.
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