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

作者：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^*

来源：Nature Neuroscience, 2012, 15(4): 574-580.

DOI：10.1038/nn.3054

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, Delta N-Bcl-x(L). We found that ABT-737 administered before or after ischemia inhibited Delta N-Bcl-x(L)-induced mitochondrial channel activity and neuronal death. To establish a causal role for Delta N-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.

• 出版日期2012-4