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

doi:10.1038/nn.3054

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

Neuroscience

Research output: Contribution to journal › Article › peer-review

58 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 language	English (US)
Pages (from-to)	574-580
Number of pages	7
Journal	Nature Neuroscience
Volume	15
Issue number	4
DOIs	https://doi.org/10.1038/nn.3054
State	Published - Apr 2012

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Neuroscience(all)

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@article{825f8cdbe251419cb8d29b75d0591c11,

title = "N-terminally cleaved Bcl-x L mediates ischemia-induced neuronal death",

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.",

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

note = "Funding Information: We thank A. Latuszek-Barrantes for excellent technical assistance, and J. Hickman, R. Kitsis and L.K. Kaczmarek for insightful scientific discussion and constructive review of the manuscript. We thank C. Kinnally and N. Danial for the gift of Bax−/−; Bak−/− MEFs and the Institut de Recherches Servier for ABT-737. This work was supported by grants from the US National Institutes of Health (NS045876 to E.A.J., NS46742 to R.S.Z. and NS37402 to J.M.H.), a McKnight Foundation Brain Disorders Award (to R.S.Z.) and a generous grant from the F.M. Kirby Foundation (to R.S.Z.). R.S.Z. is the F.M. Kirby Professor of Neural Repair and Protection.",

year = "2012",

month = apr,

doi = "10.1038/nn.3054",

language = "English (US)",

volume = "15",

pages = "574--580",

journal = "Nature Neuroscience",

issn = "1097-6256",

publisher = "Nature Publishing Group",

number = "4",

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TY - JOUR

T1 - N-terminally cleaved Bcl-x L mediates ischemia-induced neuronal death

AU - Ofengeim, Dimitry

AU - Chen, Ying Bei

AU - Miyawaki, Takahiro

AU - Li, Hongmei

AU - Sacchetti, Silvio

AU - Flannery, Richard J.

AU - Alavian, Kambiz N.

AU - Pontarelli, Fabrizio

AU - Roelofs, Brian A.

AU - Hickman, John A.

AU - Hardwick, J. Marie

AU - Zukin, R. Suzanne

AU - Jonas, Elizabeth A.

N1 - Funding Information: We thank A. Latuszek-Barrantes for excellent technical assistance, and J. Hickman, R. Kitsis and L.K. Kaczmarek for insightful scientific discussion and constructive review of the manuscript. We thank C. Kinnally and N. Danial for the gift of Bax−/−; Bak−/− MEFs and the Institut de Recherches Servier for ABT-737. This work was supported by grants from the US National Institutes of Health (NS045876 to E.A.J., NS46742 to R.S.Z. and NS37402 to J.M.H.), a McKnight Foundation Brain Disorders Award (to R.S.Z.) and a generous grant from the F.M. Kirby Foundation (to R.S.Z.). R.S.Z. is the F.M. Kirby Professor of Neural Repair and Protection.

PY - 2012/4

Y1 - 2012/4

N2 - 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.

AB - 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.

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U2 - 10.1038/nn.3054

DO - 10.1038/nn.3054

M3 - Article

C2 - 22366758

AN - SCOPUS:84862777042

SN - 1097-6256

VL - 15

SP - 574

EP - 580

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 4

ER -

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

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