Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Park, Han-A, Jonas, Elizabeth A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Medknow Publications & Media Pvt Ltd 2017
Materias:
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
_version_ 1783288981063991296
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
work_keys_str_mv AT parkhana dnbclxlatherapeutictargetforneuroprotection
AT jonaselizabetha dnbclxlatherapeutictargetforneuroprotection