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ΔN-Bcl-xL, a therapeutic target for neuroprotection
The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitoch...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Medknow Publications & Media Pvt Ltd
2017
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745825/ https://www.ncbi.nlm.nih.gov/pubmed/29239317 http://dx.doi.org/10.4103/1673-5374.219033 |
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author | Park, Han-A Jonas, Elizabeth A. |
author_facet | Park, Han-A Jonas, Elizabeth A. |
author_sort | Park, Han-A |
collection | PubMed |
description | The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-Bcl-xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-xL by glutamate, overexpression of ΔN-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-xL is a central target for interventions. |
format | Online Article Text |
id | pubmed-5745825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Medknow Publications & Media Pvt Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-57458252018-01-02 ΔN-Bcl-xL, a therapeutic target for neuroprotection Park, Han-A Jonas, Elizabeth A. Neural Regen Res Invited Review The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-Bcl-xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-xL by glutamate, overexpression of ΔN-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-xL is a central target for interventions. Medknow Publications & Media Pvt Ltd 2017-11 /pmc/articles/PMC5745825/ /pubmed/29239317 http://dx.doi.org/10.4103/1673-5374.219033 Text en Copyright: © Neural Regeneration Research http://creativecommons.org/licenses/by-nc-sa/3.0 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. |
spellingShingle | Invited Review Park, Han-A Jonas, Elizabeth A. ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title | ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title_full | ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title_fullStr | ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title_full_unstemmed | ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title_short | ΔN-Bcl-xL, a therapeutic target for neuroprotection |
title_sort | δn-bcl-xl, a therapeutic target for neuroprotection |
topic | Invited Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745825/ https://www.ncbi.nlm.nih.gov/pubmed/29239317 http://dx.doi.org/10.4103/1673-5374.219033 |
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