Suppression of the intrinsic apoptosis pathway by sinaptic activity

Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-...

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Authors: Léveillé, Frédéric, Papadia, Sofia, Fricker, Michael, Bell, Karen F. S., Soriano Zaragoza, Francesc X. (Francesc Xavier), Martel, Marc-André, Puddifoot, Clare, Habel, Marlen, Wyllie, David J. A., Ikonomidou, Chrysanthy, Tolkovsky, Aviva M., Hardingham, Giles E.
Format: article
Status:Published version
Publication Date:2010
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/60800
Online Access:https://hdl.handle.net/2445/60800
Access Level:Open access
Keyword:Neurones
Regulació genètica
Apoptosi
Sinapsi
Neurons
Genetic regulation
Apoptosis
Synapses
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spelling Suppression of the intrinsic apoptosis pathway by sinaptic activityLéveillé, FrédéricPapadia, SofiaFricker, MichaelBell, Karen F. S.Soriano Zaragoza, Francesc X. (Francesc Xavier)Martel, Marc-AndréPuddifoot, ClareHabel, MarlenWyllie, David J. A.Ikonomidou, ChrysanthyTolkovsky, Aviva M.Hardingham, Giles E.NeuronesRegulació genèticaApoptosiSinapsiNeuronsGenetic regulationApoptosisSynapsesSynaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.The Society for Neuroscience2014201420102014info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion13 p.application/pdfhttps://hdl.handle.net/2445/60800Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1523/JNEUROSCI.5115-09.2010Journal of Neuroscience, 2010, vol. 30, num. 7, p. 2623-2635http://dx.doi.org/10.1523/JNEUROSCI.5115-09.2010cc-by-nc-sa (c) Léveillé, F. et al., 2010http://creativecommons.org/licenses/by-nc-sa/3.0/esinfo:eu-repo/semantics/openAccessoai:recercat.cat:2445/608002026-05-29T05:05:01Z
dc.title.none.fl_str_mv Suppression of the intrinsic apoptosis pathway by sinaptic activity
title Suppression of the intrinsic apoptosis pathway by sinaptic activity
spellingShingle Suppression of the intrinsic apoptosis pathway by sinaptic activity
Léveillé, Frédéric
Neurones
Regulació genètica
Apoptosi
Sinapsi
Neurons
Genetic regulation
Apoptosis
Synapses
title_short Suppression of the intrinsic apoptosis pathway by sinaptic activity
title_full Suppression of the intrinsic apoptosis pathway by sinaptic activity
title_fullStr Suppression of the intrinsic apoptosis pathway by sinaptic activity
title_full_unstemmed Suppression of the intrinsic apoptosis pathway by sinaptic activity
title_sort Suppression of the intrinsic apoptosis pathway by sinaptic activity
dc.creator.none.fl_str_mv Léveillé, Frédéric
Papadia, Sofia
Fricker, Michael
Bell, Karen F. S.
Soriano Zaragoza, Francesc X. (Francesc Xavier)
Martel, Marc-André
Puddifoot, Clare
Habel, Marlen
Wyllie, David J. A.
Ikonomidou, Chrysanthy
Tolkovsky, Aviva M.
Hardingham, Giles E.
author Léveillé, Frédéric
author_facet Léveillé, Frédéric
Papadia, Sofia
Fricker, Michael
Bell, Karen F. S.
Soriano Zaragoza, Francesc X. (Francesc Xavier)
Martel, Marc-André
Puddifoot, Clare
Habel, Marlen
Wyllie, David J. A.
Ikonomidou, Chrysanthy
Tolkovsky, Aviva M.
Hardingham, Giles E.
author_role author
author2 Papadia, Sofia
Fricker, Michael
Bell, Karen F. S.
Soriano Zaragoza, Francesc X. (Francesc Xavier)
Martel, Marc-André
Puddifoot, Clare
Habel, Marlen
Wyllie, David J. A.
Ikonomidou, Chrysanthy
Tolkovsky, Aviva M.
Hardingham, Giles E.
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Neurones
Regulació genètica
Apoptosi
Sinapsi
Neurons
Genetic regulation
Apoptosis
Synapses
topic Neurones
Regulació genètica
Apoptosi
Sinapsi
Neurons
Genetic regulation
Apoptosis
Synapses
description Synaptic activity promotes resistance to diverse apoptotic insults, the mechanism behind which is incompletely understood. We show here that a coordinated downregulation of core components of the intrinsic apoptosis pathway by neuronal activity forms a key part of the underlying mechanism. Activity-dependent protection against apoptotic insults is associated with inhibition of cytochrome c release in most but not all neurons, indicative of anti-apoptotic signaling both upstream and downstream of this step. We find that enhanced firing activity suppresses expression of the proapoptotic BH3-only member gene Puma in a NMDA receptor-dependent, p53-independent manner. Puma expression is sufficient to induce cytochrome c loss and neuronal apoptosis. Puma deficiency protects neurons against apoptosis and also occludes the protective effect of synaptic activity, while blockade of physiological NMDA receptor activity in the developing mouse brain induces neuronal apoptosis that is preceded by upregulation of Puma. However, enhanced activity can also confer resistance to Puma-induced apoptosis, acting downstream of cytochrome c release. This mechanism is mediated by transcriptional suppression of apoptosome components Apaf-1 and procaspase-9, and limiting caspase-9 activity, since overexpression of procaspase-9 accelerates the rate of apoptosis in active neurons back to control levels. Synaptic activity does not exert further significant anti-apoptotic effects downstream of caspase-9 activation, since an inducible form of caspase-9 overrides the protective effect of synaptic activity, despite activity-induced transcriptional suppression of caspase-3. Thus, suppression of apoptotic gene expression may synergize with other activity-dependent events such as enhancement of antioxidant defenses to promote neuronal survival.
publishDate 2010
dc.date.none.fl_str_mv 2010
2014
2014
2014
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/60800
url https://hdl.handle.net/2445/60800
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1523/JNEUROSCI.5115-09.2010
Journal of Neuroscience, 2010, vol. 30, num. 7, p. 2623-2635
http://dx.doi.org/10.1523/JNEUROSCI.5115-09.2010
dc.rights.none.fl_str_mv cc-by-nc-sa (c) Léveillé, F. et al., 2010
http://creativecommons.org/licenses/by-nc-sa/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc-sa (c) Léveillé, F. et al., 2010
http://creativecommons.org/licenses/by-nc-sa/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 13 p.
application/pdf
dc.publisher.none.fl_str_mv The Society for Neuroscience
publisher.none.fl_str_mv The Society for Neuroscience
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869405436917055488
score 15,81155

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