Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Abstract Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Cristina Pintado, Sandra Macías, Helena Domínguez-Martín, Angélica Castaño, Diego Ruano
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b3299f0abb2a43c7ba4660ef0b159517
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:b3299f0abb2a43c7ba4660ef0b159517
record_format	dspace
spelling	oai:doaj.org-article:b3299f0abb2a43c7ba4660ef0b1595172021-12-02T12:32:14ZNeuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation10.1038/s41598-017-08722-32045-2322https://doaj.org/article/b3299f0abb2a43c7ba4660ef0b1595172017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08722-3https://doaj.org/toc/2045-2322Abstract Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3β activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6α attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1α-mediated splicing activity, might underlie in vivo ATF6α attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic feature.Cristina PintadoSandra MacíasHelena Domínguez-MartínAngélica CastañoDiego RuanoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristina Pintado Sandra Macías Helena Domínguez-Martín Angélica Castaño Diego Ruano Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
description	Abstract Proteostasis alteration and neuroinflammation are typical features of normal aging. We have previously shown that neuroinflammation alters cellular proteostasis through immunoproteasome induction, leading to a transient decrease of proteasome activity. Here, we further investigated the role of acute lipopolysaccharide (LPS)-induced hippocampal neuroinflammation in cellular proteostasis. In particular, we focused on macroautophagy (hereinafter called autophagy) and endoplasmic reticulum-associated protein degradation (ERAD). We demonstrate that LPS injection induced autophagy activation that was dependent, at least in part, on glycogen synthase kinase (GSK)-3β activity but independent of mammalian target of rapamycin (mTOR) inhibition. Neuroinflammation also produced endoplasmic reticulum (ER) stress leading to canonical unfolded protein response (UPR) activation with a rapid activating transcription factor (ATF) 6α attenuation that resulted in a time-dependent down-regulation of ERAD markers. In this regard, the time-dependent accumulation of unspliced X-box binding protein (XBP) 1, likely because of decreased inositol-requiring enzyme (IRE) 1α-mediated splicing activity, might underlie in vivo ATF6α attenuation. Importantly, lactacystin-induced activation of ERAD was abolished in both the acute neuroinflammation model and in aged rats. Therefore, we provide a cellular pathway through which neuroinflammation might sensitize cells to neurodegeneration under stress situations, being relevant in normal aging and other disorders where neuroinflammation is a characteristic feature.
format	article
author	Cristina Pintado Sandra Macías Helena Domínguez-Martín Angélica Castaño Diego Ruano
author_facet	Cristina Pintado Sandra Macías Helena Domínguez-Martín Angélica Castaño Diego Ruano
author_sort	Cristina Pintado
title	Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
title_short	Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
title_full	Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
title_fullStr	Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
title_full_unstemmed	Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation
title_sort	neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting erad activation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b3299f0abb2a43c7ba4660ef0b159517
work_keys_str_mv	AT cristinapintado neuroinflammationalterscellularproteostasisbyproducingendoplasmicreticulumstressautophagyactivationanddisruptingeradactivation AT sandramacias neuroinflammationalterscellularproteostasisbyproducingendoplasmicreticulumstressautophagyactivationanddisruptingeradactivation AT helenadominguezmartin neuroinflammationalterscellularproteostasisbyproducingendoplasmicreticulumstressautophagyactivationanddisruptingeradactivation AT angelicacastano neuroinflammationalterscellularproteostasisbyproducingendoplasmicreticulumstressautophagyactivationanddisruptingeradactivation AT diegoruano neuroinflammationalterscellularproteostasisbyproducingendoplasmicreticulumstressautophagyactivationanddisruptingeradactivation
_version_	1718394178760605696

Neuroinflammation alters cellular proteostasis by producing endoplasmic reticulum stress, autophagy activation and disrupting ERAD activation

Ejemplares similares