Journal
CELL DEATH AND DIFFERENTIATION
Volume 14, Issue 5, Pages 1011-1019Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cdd.4402089
Keywords
apoptosis; apaf-1; apoptosome; caspase; ER stress; Neurons; caspase
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Funding
- NINDS NIH HHS [NS42197] Funding Source: Medline
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Apoptosis triggered by endoplasmic reticulum ( ER) stress is associated with various pathophysiological conditions including neurodegenerative diseases and ischemia. However, the mechanism by which ER stress induces neuronal apoptosis remains controversial. Here we identify the pathway of apoptosis carried out in sympathetic neurons triggered to die by ER stress- inducing agent tunicamycin. We find that ER stress induces a neuronal apoptotic pathway which upregulates BH3- only genes DP5 and Puma. Importantly, we show that ER stress commits neurons to die before cytochrome c release and this commitment requires Bax activation and c- jun N- terminal kinase signaling. Furthermore, ER stress engages the mitochondrial pathway of death as neurons release cytochrome c and Apaf- 1 deficiency is sufficient to block apoptosis. Our findings identify a critical function of Bax in committing neurons to ER stress- induced apoptosis and clarify the importance of the apoptosome as the non- redundant caspase activation pathway to execute neuronal apoptosis in response to ER stress.
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