Brain-derived neurotrophic factor suppresses tunicamycin-induced upregulation of CHOP in neurons

✍ Scribed by Gang Chen; Zhiqin Fan; Xin Wang; Cuiling Ma; Kimberly A. Bower; Xianglin Shi; Zun-Ji Ke; Jia Luo

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 565 KB
• Volume: 85
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21292

✦ Synopsis

Abstract

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen triggers ER stress. ER stress initiates a number of specific compensatory signaling pathways including unfolded protein response (UPR). UPR is characterized by translational attenuation, synthesis of ER chaperone proteins such as glucose‐regulated protein of 78 kDa (GRP78, also known as Bip), and transcriptional induction, which includes the activation of transcription factors such as activating transcriptional factor 6 (ATF6) and C/EBP homologous protein (CHOP, also known as growth arrest and DNA damage‐inducible gene 153 [GADD153]). Sustained ER stress ultimately leads to cell death. ER functions are believed to be impaired in various neurodegenerative diseases, as well as in some acute disorders of the brain. Brain‐derived neurotrophic factor (BDNF), a member of the neurotrophin family, functions as a neuroprotective agent and rescues neurons from various insults. The molecular mechanisms underlying BDNF neuroprotection, however, remain to be elucidated. We showed that CHOP partially mediated ER stress‐induced neuronal death. BDNF suppressed ER stress‐induced upregulation/ nuclear translocation of CHOP. The transcription of CHOP is regulated by ATF4, ATF6, and XBP1; BDNF selectively blocked the ATF6/CHOP pathway. Furthermore, BDNF inhibited the induction of death receptor 5 (DR5), a transcriptional target of CHOP. Our study thus suggests that suppression of CHOP activation may contribute to BDNF‐mediated neuroprotection during ER stress responses. © 2007 Wiley‐Liss, Inc.