Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5846049 | Toxicology and Applied Pharmacology | 2015 | 11 Pages |
Abstract
Accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) causes ER stress, resulting in the activation of the unfolded protein response (UPR). ER stress and UPR are associated with many neurodevelopmental and neurodegenerative disorders. The developing brain is particularly susceptible to environmental insults which may cause ER stress. We evaluated the UPR in the brain of postnatal mice. Tunicamycin, a commonly used ER stress inducer, was administered subcutaneously to mice of postnatal days (PDs) 4, 12 and 25. Tunicamycin caused UPR in the cerebral cortex, hippocampus and cerebellum of mice of PD4 and PD12, which was evident by the upregulation of ATF6, XBP1s, p-eIF2α, GRP78, GRP94 and MANF, but failed to induce UPR in the brain of PD25 mice. Tunicamycin-induced UPR in the liver was observed at all stages. In PD4 mice, tunicamycin-induced caspase-3 activation was observed in layer II of the parietal and optical cortex, CA1-CA3 and the subiculum of the hippocampus, the cerebellar external germinal layer and the superior/inferior colliculus. Tunicamycin-induced caspase-3 activation was also shown on PD12 but to a much lesser degree and mainly located in the dentate gyrus of the hippocampus, deep cerebellar nuclei and pons. Tunicamycin did not activate caspase-3 in the brain of PD25 mice and the liver of all stages. Similarly, immature cerebellar neurons were sensitive to tunicamycin-induced cell death in culture, but became resistant as they matured in vitro. These results suggest that the UPR is developmentally regulated and the immature brain is more susceptible to ER stress.
Keywords
WFsCGNsintracerebroventricularICVUPRFASDNSCsDAPIERADEGLGFAPDABIACUCDCN3,3′-diaminobenzidineMTTFetal alcohol spectrum disordersEndoplasmic reticulum stressamyotrophic lateral sclerosisIGLAlzheimer's diseaseALSHuntington's diseaseProtein degradationendoplasmic reticulum-associated degradationintraperitoneal injectionApoptosisDIVDevelopmentdays in vitropostnatal daySUBsubcutaneousSubiculumInstitutional Animal Care and Use CommitteeNeural stem cellsWolfram syndromeendoplasmic reticulumdentate gyrusexternal germinal layerinternal granule layercerebellar granule neuronsdeep cerebellar nucleusUnfolded protein responseGlial fibrillary acidic protein
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Authors
Haiping Wang, Xin Wang, Zun-Ji Ke, Ashley L. Comer, Mei Xu, Jacqueline A. Frank, Zhuo Zhang, Xianglin Shi, Jia Luo,