Neuronal induction of the immunoproteasome in Huntington's disease

Huntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasom...

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Autores: Díaz-Hernández, Miguel, Hernández, Félix, Martín-Aparicio, Ester, Gómez-Ramos, Pilar, Morán, María A., Castaño, José G., Ferrer, Isidro, Ávila, Jesús, Lucas, José Javier
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2003
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/251569
Acceso en línea:http://hdl.handle.net/10261/251569
Access Level:acceso abierto
Palabra clave:Huntington’s disease
Proteasome activity
HD postmortem brain
Conditional transgenic mouse model
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spelling Neuronal induction of the immunoproteasome in Huntington's diseaseDíaz-Hernández, MiguelHernández, FélixMartín-Aparicio, EsterGómez-Ramos, PilarMorán, María A.Castaño, José G.Ferrer, IsidroÁvila, JesúsLucas, José JavierHuntington’s diseaseProteasome activityHD postmortem brainConditional transgenic mouse modelHuntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasome activity is impaired in vivo, we performed enzymatic assays for the three peptidase activities of the proteasome in brain extracts from the HD94 conditional mouse model of HD. We found no inhibition of any of the activities, suggesting that if UPS impairment happens in vivo, it is not at the level of the proteasome catalytic core. Intriguingly, the chymotrypsin- and trypsin-like activities increased selectively in the affected and aggregate-containing regions: cortex and striatum. Western blot analysis revealed no difference in total proteasome content whereas an increase in the interferon-inducible subunits of the immunoproteasome, LMP2 and LMP7, was observed. These subunits confer to the proteasome catalytic properties that are optimal for MHC-I peptide presentation. Immunohistochemistry in control mouse brain revealed LMP2 and LMP7 mainly in neurons. Accordingly, their increase in HD94 mice predominantly took place in neurons, and 5% of the ubiquitin-positive cortical aggregates were also LMP2-positive. Ultrastructural analysis of neurons with high level of immunoproteasome subunits revealed signs of neurodegeneration like nuclear indentation or fragmentation and dark cell appearance. The neuronal induction of LMP2 and LMP7 and the associated signs of neurodegeneration were also found in HD postmortem brains. Our results indicate that LMP2 and LMP7 participate in normal neuronal physiology and suggest a role in HD neurodegeneration.This work was supported by grants from Comunidad Autónoma de Madrid, Asociación Española de Corea de Huntington (ACHE), Fundación “La Caixa”, Spanish Comisión Interministerial de Ciencia y Tecnología, and by an institutional grant from Fundación Ramón Areces. E.M.-A. was the recipient of predoctoral fellowships from ACHE and Fundación Ferrer. M.D.-H. is the recipient of a postdoctoral fellowship from Comunidad Autónoma de Madrid.Peer reviewedSociety for NeuroscienceComisión Interministerial de Ciencia y Tecnología, CICYT (España)Fundación la CaixaFundación Ramón ArecesComunidad de MadridFundación Vicente FerrerConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202120212003info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/251569reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttps://doi.org/10.1523/JNEUROSCI.23-37-11653.2003Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2515692026-05-22T06:33:51Z
dc.title.none.fl_str_mv Neuronal induction of the immunoproteasome in Huntington's disease
title Neuronal induction of the immunoproteasome in Huntington's disease
spellingShingle Neuronal induction of the immunoproteasome in Huntington's disease
Díaz-Hernández, Miguel
Huntington’s disease
Proteasome activity
HD postmortem brain
Conditional transgenic mouse model
title_short Neuronal induction of the immunoproteasome in Huntington's disease
title_full Neuronal induction of the immunoproteasome in Huntington's disease
title_fullStr Neuronal induction of the immunoproteasome in Huntington's disease
title_full_unstemmed Neuronal induction of the immunoproteasome in Huntington's disease
title_sort Neuronal induction of the immunoproteasome in Huntington's disease
dc.creator.none.fl_str_mv Díaz-Hernández, Miguel
Hernández, Félix
Martín-Aparicio, Ester
Gómez-Ramos, Pilar
Morán, María A.
Castaño, José G.
Ferrer, Isidro
Ávila, Jesús
Lucas, José Javier
author Díaz-Hernández, Miguel
author_facet Díaz-Hernández, Miguel
Hernández, Félix
Martín-Aparicio, Ester
Gómez-Ramos, Pilar
Morán, María A.
Castaño, José G.
Ferrer, Isidro
Ávila, Jesús
Lucas, José Javier
author_role author
author2 Hernández, Félix
Martín-Aparicio, Ester
Gómez-Ramos, Pilar
Morán, María A.
Castaño, José G.
Ferrer, Isidro
Ávila, Jesús
Lucas, José Javier
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Comisión Interministerial de Ciencia y Tecnología, CICYT (España)
Fundación la Caixa
Fundación Ramón Areces
Comunidad de Madrid
Fundación Vicente Ferrer
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Huntington’s disease
Proteasome activity
HD postmortem brain
Conditional transgenic mouse model
topic Huntington’s disease
Proteasome activity
HD postmortem brain
Conditional transgenic mouse model
description Huntington's disease (HD) inclusions are stained with anti-ubiquitin and anti-proteasome antibodies. This, together with proteasome activity studies on transfected cells, suggest that an impairment of the ubiquitin-proteasome system (UPS) may be key in HD pathogenesis. To test whether proteasome activity is impaired in vivo, we performed enzymatic assays for the three peptidase activities of the proteasome in brain extracts from the HD94 conditional mouse model of HD. We found no inhibition of any of the activities, suggesting that if UPS impairment happens in vivo, it is not at the level of the proteasome catalytic core. Intriguingly, the chymotrypsin- and trypsin-like activities increased selectively in the affected and aggregate-containing regions: cortex and striatum. Western blot analysis revealed no difference in total proteasome content whereas an increase in the interferon-inducible subunits of the immunoproteasome, LMP2 and LMP7, was observed. These subunits confer to the proteasome catalytic properties that are optimal for MHC-I peptide presentation. Immunohistochemistry in control mouse brain revealed LMP2 and LMP7 mainly in neurons. Accordingly, their increase in HD94 mice predominantly took place in neurons, and 5% of the ubiquitin-positive cortical aggregates were also LMP2-positive. Ultrastructural analysis of neurons with high level of immunoproteasome subunits revealed signs of neurodegeneration like nuclear indentation or fragmentation and dark cell appearance. The neuronal induction of LMP2 and LMP7 and the associated signs of neurodegeneration were also found in HD postmortem brains. Our results indicate that LMP2 and LMP7 participate in normal neuronal physiology and suggest a role in HD neurodegeneration.
publishDate 2003
dc.date.none.fl_str_mv 2003
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/251569
url http://hdl.handle.net/10261/251569
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv https://doi.org/10.1523/JNEUROSCI.23-37-11653.2003
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Society for Neuroscience
publisher.none.fl_str_mv Society for Neuroscience
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812455

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