Abstract
The mechanism of endoplasmic reticulum (ER)-mediated apoptosis in neurons was examined. Using primary cortical neurons, we show that nordihydroguaiaretic acid (NDGA) and brefeldin A (BFA), two ER stressors, induce early ER stress as shown by Western blotting of the eukaryotic initiation factor-2alpha (eIF2alpha), an ER stress marker. This event was associated with an enhancement of neuronal apoptosis as demonstrated by the time-dependent increase in caspase-3 activity and by nuclear fragmentation. The study of the apoptotic signaling showed the translocation of cytochrome c from the mitochondrial matrix to the cytosol. Further evaluation of the apoptotic process revealed that NDGA and BFA induced a rapid dephosphorylation of BAD and decrease expression of Bcl-2. Altogether, our results indicate that neuronal ER stress is associated with an apoptotic cascade involving the mitochondria.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antioxidants / pharmacology
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Apoptosis / physiology*
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Brefeldin A / pharmacology
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Carrier Proteins / metabolism*
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Caspase 3
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Caspases / metabolism
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Cell Fractionation
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Cell Nucleus / metabolism
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Cells, Cultured
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Cerebral Cortex / cytology
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Cerebral Cortex / metabolism
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism*
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Enzyme Activation
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Eukaryotic Initiation Factor-2 / metabolism
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Masoprocol / pharmacology
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Mitochondria / metabolism*
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Neurons / cytology
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Neurons / drug effects
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Neurons / metabolism*
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Protein Synthesis Inhibitors / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / metabolism*
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Rats
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Rats, Sprague-Dawley
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bcl-Associated Death Protein
Substances
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Antioxidants
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Bad protein, rat
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Carrier Proteins
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Eukaryotic Initiation Factor-2
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Protein Synthesis Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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bcl-Associated Death Protein
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Brefeldin A
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Masoprocol
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Casp3 protein, rat
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Caspase 3
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Caspases