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

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, a causal role of these events in ischemia-induced neuronal death is unclear. Un...

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Autores principales: Ofengeim, Dimitry, Chen, Yingbei, 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862259/
https://www.ncbi.nlm.nih.gov/pubmed/22366758
http://dx.doi.org/10.1038/nn.3054
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author Ofengeim, Dimitry
Chen, Yingbei
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.
author_facet Ofengeim, Dimitry
Chen, Yingbei
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.
author_sort Ofengeim, Dimitry
collection PubMed
description 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, a causal role of these events in ischemia-induced neuronal death is unclear. Unexpectedly, we found that the Bcl-2/Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protects 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 knockin mice expressing caspase-resistant Bcl-x(L). The knockin mice exhibit strikingly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings point to truncated Bcl-x(L) as a potentially important therapeutic target in ischemic brain injury.
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spelling pubmed-38622592013-12-13 N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death Ofengeim, Dimitry Chen, Yingbei 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. Nat Neurosci Article 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, a causal role of these events in ischemia-induced neuronal death is unclear. Unexpectedly, we found that the Bcl-2/Bcl-x(L) inhibitor ABT-737, which enhances death of tumor cells, protects 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 knockin mice expressing caspase-resistant Bcl-x(L). The knockin mice exhibit strikingly reduced mitochondrial channel activity and reduced vulnerability to ischemia-induced neuronal death. These findings point to truncated Bcl-x(L) as a potentially important therapeutic target in ischemic brain injury. 2012-02-26 /pmc/articles/PMC3862259/ /pubmed/22366758 http://dx.doi.org/10.1038/nn.3054 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Ofengeim, Dimitry
Chen, Yingbei
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.
N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title_full N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title_fullStr N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title_full_unstemmed N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title_short N-terminally cleaved Bcl-x(L) mediates ischemia-induced neuronal death
title_sort n-terminally cleaved bcl-x(l) mediates ischemia-induced neuronal death
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3862259/
https://www.ncbi.nlm.nih.gov/pubmed/22366758
http://dx.doi.org/10.1038/nn.3054
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