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...
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| Format: | Article |
| Language: | English |
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Wolters Kluwer Medknow Publications
2017-01-01
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| Series: | Neural Regeneration Research |
| Subjects: | |
| Online Access: | http://www.nrronline.org/article.asp?issn=1673-5374;year=2017;volume=12;issue=11;spage=1791;epage=1794;aulast=Park |
| _version_ | 1818307106544025600 |
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| author | Han-A Park Elizabeth A Jonas |
| author_facet | Han-A Park Elizabeth A Jonas |
| author_sort | Han-A Park |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-13T06:53:06Z |
| format | Article |
| id | doaj.art-ff1c8c3f91ad4b5bb626fd0c654ae473 |
| institution | Directory Open Access Journal |
| issn | 1673-5374 |
| language | English |
| last_indexed | 2024-12-13T06:53:06Z |
| publishDate | 2017-01-01 |
| publisher | Wolters Kluwer Medknow Publications |
| record_format | Article |
| series | Neural Regeneration Research |
| spelling | doaj.art-ff1c8c3f91ad4b5bb626fd0c654ae4732022-12-21T23:56:06ZengWolters Kluwer Medknow PublicationsNeural Regeneration Research1673-53742017-01-0112111791179410.4103/1673-5374.219033ΔN-Bcl-xL, a therapeutic target for neuroprotectionHan-A ParkElizabeth A JonasThe 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.http://www.nrronline.org/article.asp?issn=1673-5374;year=2017;volume=12;issue=11;spage=1791;epage=1794;aulast=ParkB-cell lymphoma-extra large; ΔN-Bcl-xL; mitochondria; ABT-737 |
| spellingShingle | Han-A Park Elizabeth A Jonas ΔN-Bcl-xL, a therapeutic target for neuroprotection Neural Regeneration Research B-cell lymphoma-extra large; ΔN-Bcl-xL; mitochondria; ABT-737 |
| 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 | B-cell lymphoma-extra large; ΔN-Bcl-xL; mitochondria; ABT-737 |
| url | http://www.nrronline.org/article.asp?issn=1673-5374;year=2017;volume=12;issue=11;spage=1791;epage=1794;aulast=Park |
| work_keys_str_mv | AT hanapark dnbclxlatherapeutictargetforneuroprotection AT elizabethajonas dnbclxlatherapeutictargetforneuroprotection |