期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 24, 期 1, 页码 328-341出版社
WILEY
DOI: 10.1111/jcmm.14732
关键词
autophagy; endoplasmic reticulum stress; manganese; neurotoxicity; PERK signalling pathway
资金
- National Natural Science Foundation of China [81773377]
Overexposure to manganese (Mn) is neurotoxic. Our previous research has demonstrated that the interaction of endoplasmic reticulum (ER) stress and autophagy participates in the early stage of Mn-mediated neurotoxicity in mouse. However, the mechanisms of ER stress signalling pathways in the initiation of autophagy remain confused. In the current study, we first validated that ER stress-mediated cell apoptosis is accompanied by autophagy in SH-SY5Y cells. Then, we found that inhibiting ER stress with 4-phenylbutyrate (4-PBA) decreased ER stress-related protein expression and reduced cell apoptosis, whereas blocking autophagy with 3-methyladenine (3-MA) increased cell apoptosis. These data indicate that protective autophagy was activated to alleviate ER stress-mediated apoptosis. Knockdown of the protein kinase RNA-like ER kinase (PERK) gene inhibited Mn-induced autophagy and weakened the interaction between ATF4 and the LC3 promoter. Our results reveal a novel molecular mechanism in which ER stress may regulate autophagy via the PERK/eIF2 alpha/ATF4 signalling pathway. Additionally, Mn may activate protective autophagy to alleviate ER stress-mediated apoptosis via the PERK/eIF2 alpha/ATF4 signalling pathway in SH-SY5Y cells.
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