Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis* / drug effects
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Apoptotic Protease-Activating Factor 1 / metabolism*
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Caspases / metabolism
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Cell Lineage*
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Cell Survival / drug effects
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Cells, Cultured
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Cytochromes c / metabolism
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / pathology*
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Enzyme Activation / drug effects
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase Kinases / metabolism
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Mice
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Neurons / cytology*
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Neurons / drug effects
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Neurons / metabolism*
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Signal Transduction / drug effects
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Time Factors
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tunicamycin / pharmacology
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Up-Regulation / drug effects
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bcl-2-Associated X Protein / deficiency
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bcl-2-Associated X Protein / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Apoptotic Protease-Activating Factor 1
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Hrk protein, mouse
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Neuropeptides
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PUMA protein, mouse
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Tumor Suppressor Proteins
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bcl-2-Associated X Protein
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Tunicamycin
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Cytochromes c
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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Map3k9 protein, mouse
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Caspases