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.
Original language | English |
---|---|
Pages (from-to) | 1674-1684 |
Number of pages | 11 |
Journal | Journal of Neuroscience Research |
Volume | 85 |
Issue number | 8 |
DOIs | |
State | Published - Jun 2007 |
Keywords
- Cell death
- Endoplasmic reticulum stress
- Neurodegeneration
- Neuroprotection
- Neurotrophic factor
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience