Journal
CELL DEATH & DISEASE
Volume 6, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cddis.2015.90
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Funding
- [24390421]
- [25462921]
- Grants-in-Aid for Scientific Research [25462921] Funding Source: KAKEN
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The signaling pathway leading to the endoplasmic reticulum (ER) stress responses has not been fully elucidated. Here we showed that glycogen synthase kinase-3 beta (GSK-3 beta)-dependent downregulation of gamma-taxilin and nascent polypeptide-associated complex alpha-subunit (alpha NAC) mediates hypoxia-induced unfolded protein responses (UPRs) and the subsequent apoptotic and autophagic pathways. The degradation of gamma-taxilin or alpha NAC was sufficient to initiate UPRs in normoxic cells. However, the ER stress signaling pathways initiated by gamma-taxilin or alpha NAC were distinct, triggering different ER stress sensors and activating different downstream pathways. Hypoxia caused GSK-3 beta-dependent tau hyperphosphorylation and cleavage in neuronal cells, but gamma-taxilin ablation induced tau hyperphosphorylation alone and alpha NAC ablation induced neither changes. Notably, downregulation of gamma-taxilin and alpha NAC occurs in the brain of patients with Alzheimer's disease. These results suggest that GSK-3 beta-dependent downregulation of gamma-taxilin and alpha NAC, which differently activate the UPRs, merge to regulate hypoxia-induced ER stress responses and provide a new insight into the pathogenesis of neurodegenerative diseases.
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