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- Title
N-terminally cleaved Bcl-x<sub>L</sub> mediates ischemia-induced neuronal death.
- Authors
Ofengeim, Dimitry; Chen, Ying-bei; Miyawaki, Takahiro; Li, Hongmei; Sacchetti, Silvio; Flannery, Richard J; Alavian, Kambiz N; Pontarelli, Fabrizio; Roelofs, Brian A; Hickman, John A; Hardwick, J Marie; Zukin, R Suzanne; Jonas, Elizabeth A
- 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-xL inhibitor ABT-737, which enhances death of tumor cells, protected rats against neuronal death in a clinically relevant model of brain ischemia. Bcl-xL is prominently expressed in adult neurons and can be cleaved by caspases to generate a pro-death fragment, ?N-Bcl-xL. We found that ABT-737 administered before or after ischemia inhibited ?N-Bcl-xL-induced mitochondrial channel activity and neuronal death. To establish a causal role for ?N-Bcl-xL, we generated knock-in mice expressing a caspase-resistant form of Bcl-xL. The knock-in mice exhibited markedly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings suggest that truncated Bcl-xL could be a potentially important therapeutic target in ischemic brain injury.
- Publication
Nature Neuroscience, 2012, Vol 15, Issue 4, p574
- ISSN
1097-6256
- Publication type
Academic Journal
- DOI
10.1038/nn.3054