N-terminally cleaved Bcl-x L mediates ischemia-induced neuronal death

Dimitry Ofengeim, Ying Bei Chen, Takahiro Miyawaki, Hongmei Li, Silvio Sacchetti, Richard J. Flannery, Kambiz N. Alavian, Fabrizio Pontarelli, Brian A. Roelofs, John A. Hickman, J. Marie Hardwick, R. Suzanne Zukin, Elizabeth A. Jonas

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45 Scopus citations

Abstract

Transient global ischemia in rats induces delayed death of hippocampal CA1 neurons. Early events include caspase activation, cleavage of anti-death Bcl-2 family proteins and large mitochondrial channel activity. However, whether these events have a causal role in ischemia-induced neuronal death is unclear. We found that the Bcl-2 and Bcl-x L inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-x L is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, δN-Bcl-x L. We found that ABT-737 administered before or after ischemia inhibited δN-Bcl-x L-induced mitochondrial channel activity and neuronal death. To establish a causal role for δN-Bcl-x L, we generated knock-in mice expressing a caspase-resistant form of Bcl-x L. The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-x L could be a potentially important therapeutic target in ischemic brain injury.

Original languageEnglish (US)
Pages (from-to)574-580
Number of pages7
JournalNature Neuroscience
Volume15
Issue number4
DOIs
StatePublished - Apr 1 2012

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ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Ofengeim, D., Chen, Y. B., Miyawaki, T., Li, H., Sacchetti, S., Flannery, R. J., Alavian, K. N., Pontarelli, F., Roelofs, B. A., Hickman, J. A., Hardwick, J. M., Zukin, R. S., & Jonas, E. A. (2012). N-terminally cleaved Bcl-x L mediates ischemia-induced neuronal death. Nature Neuroscience, 15(4), 574-580. https://doi.org/10.1038/nn.3054