Cargando…
Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury
BACKGROUND: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability t...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324261/ https://www.ncbi.nlm.nih.gov/pubmed/28235423 http://dx.doi.org/10.1186/s13024-017-0163-2 |
_version_ | 1782510190058274816 |
---|---|
author | Engel, Tobias Martinez-Villarreal, Jaime Henke, Christine Jimenez-Mateos, Eva M. Sanz-Rodriguez, Amaya Alves, Mariana Hernandez-Santana, Yasmina Brennan, Gary P. Kenny, Aidan Campbell, Aoife Lucas, Jose J. Henshall, David C. |
author_facet | Engel, Tobias Martinez-Villarreal, Jaime Henke, Christine Jimenez-Mateos, Eva M. Sanz-Rodriguez, Amaya Alves, Mariana Hernandez-Santana, Yasmina Brennan, Gary P. Kenny, Aidan Campbell, Aoife Lucas, Jose J. Henshall, David C. |
author_sort | Engel, Tobias |
collection | PubMed |
description | BACKGROUND: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury. METHOD: To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status epilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced dysfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitin(G76V)-green fluorescent protein. Treatment with the specific proteasome inhibitor epoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology. RESULTS AND CONCLUSIONS: Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region- and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0163-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5324261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-53242612017-03-01 Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury Engel, Tobias Martinez-Villarreal, Jaime Henke, Christine Jimenez-Mateos, Eva M. Sanz-Rodriguez, Amaya Alves, Mariana Hernandez-Santana, Yasmina Brennan, Gary P. Kenny, Aidan Campbell, Aoife Lucas, Jose J. Henshall, David C. Mol Neurodegener Research Article BACKGROUND: The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of unwanted and/or misfolded soluble proteins. This includes proteins regulating cellular survival, synaptic plasticity and neurotransmitter signaling; processes controlling excitability thresholds that are altered by epileptogenic insults. Dysfunction of the UPS has been reported to occur in a brain region- and cell-specific manner and contribute to disease progression in acute and chronic brain diseases. Prolonged seizures, status epilepticus, may alter UPS function but there has been no systematic attempt to map when and where this occurs in vivo or to determine the consequences of proteasome inhibition on seizure-induced brain injury. METHOD: To determine whether seizures lead to an impairment of the UPS, we used a mouse model of status epilepticus whereby seizures are triggered by an intra-amygdala injection of kainic acid. Status epilepticus in this model causes cell death in selected brain areas, in particular the ipsilateral CA3 subfield of the hippocampus, and the development of epilepsy after a short latent period. To monitor seizure-induced dysfunction of the UPS we used a UPS inhibition reporter mouse expressing the ubiquitin fusion degradation substrate ubiquitin(G76V)-green fluorescent protein. Treatment with the specific proteasome inhibitor epoxomicin was used to establish the impact of proteasome inhibition on seizure-induced pathology. RESULTS AND CONCLUSIONS: Our studies show that status epilepticus induced by intra-amygdala kainic acid causes select spatio-temporal UPS inhibition which is most evident in damage-resistant regions of the hippocampus, including CA1 pyramidal and dentate granule neurons then appears later in astrocytes. In support of this exerting a beneficial effect, injection of mice with the proteasome inhibitor epoxomicin protected the normally vulnerable hippocampal CA3 subfield from seizure-induced neuronal death in the model. These studies reveal brain region- and cell-specific UPS impairment occurs after seizures and suggest UPS inhibition can protect against seizure-induced brain damage. Identifying networks or pathways regulated through the proteasome after seizures may yield novel target genes for the treatment of seizure-induced cell death and possibly epilepsy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13024-017-0163-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-02-24 /pmc/articles/PMC5324261/ /pubmed/28235423 http://dx.doi.org/10.1186/s13024-017-0163-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Engel, Tobias Martinez-Villarreal, Jaime Henke, Christine Jimenez-Mateos, Eva M. Sanz-Rodriguez, Amaya Alves, Mariana Hernandez-Santana, Yasmina Brennan, Gary P. Kenny, Aidan Campbell, Aoife Lucas, Jose J. Henshall, David C. Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title | Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title_full | Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title_fullStr | Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title_full_unstemmed | Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title_short | Spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
title_sort | spatiotemporal progression of ubiquitin-proteasome system inhibition after status epilepticus suggests protective adaptation against hippocampal injury |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5324261/ https://www.ncbi.nlm.nih.gov/pubmed/28235423 http://dx.doi.org/10.1186/s13024-017-0163-2 |
work_keys_str_mv | AT engeltobias spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT martinezvillarrealjaime spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT henkechristine spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT jimenezmateosevam spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT sanzrodriguezamaya spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT alvesmariana spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT hernandezsantanayasmina spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT brennangaryp spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT kennyaidan spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT campbellaoife spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT lucasjosej spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury AT henshalldavidc spatiotemporalprogressionofubiquitinproteasomesysteminhibitionafterstatusepilepticussuggestsprotectiveadaptationagainsthippocampalinjury |