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Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives b...

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Autores principales: Scekic-Zahirovic, Jelena, Sanjuan-Ruiz, Inmaculada, Kan, Vanessa, Megat, Salim, De Rossi, Pierre, Dieterlé, Stéphane, Cassel, Raphaelle, Jamet, Marguerite, Kessler, Pascal, Wiesner, Diana, Tzeplaeff, Laura, Demais, Valérie, Sahadevan, Sonu, Hembach, Katharina M., Muller, Hans-Peter, Picchiarelli, Gina, Mishra, Nibha, Antonucci, Stefano, Dirrig-Grosch, Sylvie, Kassubek, Jan, Rasche, Volker, Ludolph, Albert, Boutillier, Anne-Laurence, Roselli, Francesco, Polymenidou, Magdalini, Lagier-Tourenne, Clotilde, Liebscher, Sabine, Dupuis, Luc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140148/
https://www.ncbi.nlm.nih.gov/pubmed/34021132
http://dx.doi.org/10.1038/s41467-021-23187-9
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author Scekic-Zahirovic, Jelena
Sanjuan-Ruiz, Inmaculada
Kan, Vanessa
Megat, Salim
De Rossi, Pierre
Dieterlé, Stéphane
Cassel, Raphaelle
Jamet, Marguerite
Kessler, Pascal
Wiesner, Diana
Tzeplaeff, Laura
Demais, Valérie
Sahadevan, Sonu
Hembach, Katharina M.
Muller, Hans-Peter
Picchiarelli, Gina
Mishra, Nibha
Antonucci, Stefano
Dirrig-Grosch, Sylvie
Kassubek, Jan
Rasche, Volker
Ludolph, Albert
Boutillier, Anne-Laurence
Roselli, Francesco
Polymenidou, Magdalini
Lagier-Tourenne, Clotilde
Liebscher, Sabine
Dupuis, Luc
author_facet Scekic-Zahirovic, Jelena
Sanjuan-Ruiz, Inmaculada
Kan, Vanessa
Megat, Salim
De Rossi, Pierre
Dieterlé, Stéphane
Cassel, Raphaelle
Jamet, Marguerite
Kessler, Pascal
Wiesner, Diana
Tzeplaeff, Laura
Demais, Valérie
Sahadevan, Sonu
Hembach, Katharina M.
Muller, Hans-Peter
Picchiarelli, Gina
Mishra, Nibha
Antonucci, Stefano
Dirrig-Grosch, Sylvie
Kassubek, Jan
Rasche, Volker
Ludolph, Albert
Boutillier, Anne-Laurence
Roselli, Francesco
Polymenidou, Magdalini
Lagier-Tourenne, Clotilde
Liebscher, Sabine
Dupuis, Luc
author_sort Scekic-Zahirovic, Jelena
collection PubMed
description Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization.
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spelling pubmed-81401482021-06-07 Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects Scekic-Zahirovic, Jelena Sanjuan-Ruiz, Inmaculada Kan, Vanessa Megat, Salim De Rossi, Pierre Dieterlé, Stéphane Cassel, Raphaelle Jamet, Marguerite Kessler, Pascal Wiesner, Diana Tzeplaeff, Laura Demais, Valérie Sahadevan, Sonu Hembach, Katharina M. Muller, Hans-Peter Picchiarelli, Gina Mishra, Nibha Antonucci, Stefano Dirrig-Grosch, Sylvie Kassubek, Jan Rasche, Volker Ludolph, Albert Boutillier, Anne-Laurence Roselli, Francesco Polymenidou, Magdalini Lagier-Tourenne, Clotilde Liebscher, Sabine Dupuis, Luc Nat Commun Article Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization. Nature Publishing Group UK 2021-05-21 /pmc/articles/PMC8140148/ /pubmed/34021132 http://dx.doi.org/10.1038/s41467-021-23187-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Scekic-Zahirovic, Jelena
Sanjuan-Ruiz, Inmaculada
Kan, Vanessa
Megat, Salim
De Rossi, Pierre
Dieterlé, Stéphane
Cassel, Raphaelle
Jamet, Marguerite
Kessler, Pascal
Wiesner, Diana
Tzeplaeff, Laura
Demais, Valérie
Sahadevan, Sonu
Hembach, Katharina M.
Muller, Hans-Peter
Picchiarelli, Gina
Mishra, Nibha
Antonucci, Stefano
Dirrig-Grosch, Sylvie
Kassubek, Jan
Rasche, Volker
Ludolph, Albert
Boutillier, Anne-Laurence
Roselli, Francesco
Polymenidou, Magdalini
Lagier-Tourenne, Clotilde
Liebscher, Sabine
Dupuis, Luc
Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title_full Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title_fullStr Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title_full_unstemmed Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title_short Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
title_sort cytoplasmic fus triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140148/
https://www.ncbi.nlm.nih.gov/pubmed/34021132
http://dx.doi.org/10.1038/s41467-021-23187-9
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