G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic

Abstract Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin po...

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Autores principales:	Thies Ingwersen, Christian Linnenberg, Emanuela D’Acunto, Shabnam Temori, Irene Paolucci, David Wasilewski, Behnam Mohammadi, Johannes Kirchmair, Robert C. Glen, Elena Miranda, Markus Glatzel, Giovanna Galliciotti
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/82d3602c215e4fa28f209ae781dcc486
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spelling	oai:doaj.org-article:82d3602c215e4fa28f209ae781dcc4862021-12-02T17:32:57ZG392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic10.1038/s41598-021-88090-12045-2322https://doaj.org/article/82d3602c215e4fa28f209ae781dcc4862021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88090-1https://doaj.org/toc/2045-2322Abstract Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin polymerization and accumulation as inclusion bodies in many cortical and subcortical neurons, thereby leading to cell death, dementia and epilepsy. Many efforts have been undertaken to elucidate the molecular pathways responsible for neuronal death. Most investigations have concentrated on analysis of intracellular mechanisms such as endoplasmic reticulum (ER) stress, ER-associated protein degradation (ERAD) and oxidative stress. We have generated a HEK-293 cell model of FENIB by overexpressing G392E-mutant neuroserpin and in this study we examine trafficking and toxicity of this polymerogenic variant. We observed that a small fraction of mutant neuroserpin is secreted via the ER-to-Golgi pathway, and that this release can be pharmacologically regulated. Overexpression of the mutant form of neuroserpin did not stimulate cell death in the HEK-293 cell model. Finally, when treating primary hippocampal neurons with G392E neuroserpin polymers, we did not detect cytotoxicity or synaptotoxicity. Altogether, we report here that a polymerogenic mutant form of neuroserpin is secreted from cells but is not toxic in the extracellular milieu.Thies IngwersenChristian LinnenbergEmanuela D’AcuntoShabnam TemoriIrene PaolucciDavid WasilewskiBehnam MohammadiJohannes KirchmairRobert C. GlenElena MirandaMarkus GlatzelGiovanna GalliciottiNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thies Ingwersen Christian Linnenberg Emanuela D’Acunto Shabnam Temori Irene Paolucci David Wasilewski Behnam Mohammadi Johannes Kirchmair Robert C. Glen Elena Miranda Markus Glatzel Giovanna Galliciotti G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
description	Abstract Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a progressive neurodegenerative disease caused by point mutations in the gene for neuroserpin, a serine protease inhibitor of the nervous system. Different mutations are known that are responsible for mutant neuroserpin polymerization and accumulation as inclusion bodies in many cortical and subcortical neurons, thereby leading to cell death, dementia and epilepsy. Many efforts have been undertaken to elucidate the molecular pathways responsible for neuronal death. Most investigations have concentrated on analysis of intracellular mechanisms such as endoplasmic reticulum (ER) stress, ER-associated protein degradation (ERAD) and oxidative stress. We have generated a HEK-293 cell model of FENIB by overexpressing G392E-mutant neuroserpin and in this study we examine trafficking and toxicity of this polymerogenic variant. We observed that a small fraction of mutant neuroserpin is secreted via the ER-to-Golgi pathway, and that this release can be pharmacologically regulated. Overexpression of the mutant form of neuroserpin did not stimulate cell death in the HEK-293 cell model. Finally, when treating primary hippocampal neurons with G392E neuroserpin polymers, we did not detect cytotoxicity or synaptotoxicity. Altogether, we report here that a polymerogenic mutant form of neuroserpin is secreted from cells but is not toxic in the extracellular milieu.
format	article
author	Thies Ingwersen Christian Linnenberg Emanuela D’Acunto Shabnam Temori Irene Paolucci David Wasilewski Behnam Mohammadi Johannes Kirchmair Robert C. Glen Elena Miranda Markus Glatzel Giovanna Galliciotti
author_facet	Thies Ingwersen Christian Linnenberg Emanuela D’Acunto Shabnam Temori Irene Paolucci David Wasilewski Behnam Mohammadi Johannes Kirchmair Robert C. Glen Elena Miranda Markus Glatzel Giovanna Galliciotti
author_sort	Thies Ingwersen
title	G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
title_short	G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
title_full	G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
title_fullStr	G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
title_full_unstemmed	G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic
title_sort	g392e neuroserpin causing the dementia fenib is secreted from cells but is not synaptotoxic
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/82d3602c215e4fa28f209ae781dcc486
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G392E neuroserpin causing the dementia FENIB is secreted from cells but is not synaptotoxic

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