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

Jelena Scekic-Zahirovic, Inmaculada Sanjuan-Ruiz, Vanessa Kan, Salim Megat, Pierre Rossi, Stéphane Dieterlé, Raphaelle Cassel, Marguerite Jamet, Pascal Kessler, Diana Wiesner, Laura Tzeplaeff, Valérie Demais, Sonu Sahadevan, Katharina M. Hembach, Hans-Peter Muller, Gina Picchiarelli, Nibha Mishra, Stefano Antonucci, Sylvie Dirrig-Grosch, Jan Kassubek, Volker Rasche, Albert Ludolph, Anne-Laurence Boutillier, Francesco Roselli, Magdalini Polymenidou, Clotilde Lagier-Tourenne, Sabine Liebscher () and Luc Dupuis ()
Additional contact information
Jelena Scekic-Zahirovic: Mécanismes centraux et périphériques de la neurodégénérescence
Inmaculada Sanjuan-Ruiz: Mécanismes centraux et périphériques de la neurodégénérescence
Vanessa Kan: Klinikum der Universität München, Ludwig-Maximilians-University Munich
Salim Megat: Mécanismes centraux et périphériques de la neurodégénérescence
Pierre Rossi: University of Zurich
Stéphane Dieterlé: Mécanismes centraux et périphériques de la neurodégénérescence
Raphaelle Cassel: Mécanismes centraux et périphériques de la neurodégénérescence
Marguerite Jamet: Mécanismes centraux et périphériques de la neurodégénérescence
Pascal Kessler: Unité mixte de service du CRBS, UMS 038
Diana Wiesner: Ulm University
Laura Tzeplaeff: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Valérie Demais: Plateforme Imagerie In Vitro, CNRS UPS-3156, NeuroPôle
Sonu Sahadevan: University of Zurich
Katharina M. Hembach: University of Zurich
Hans-Peter Muller: Ulm University
Gina Picchiarelli: Mécanismes centraux et périphériques de la neurodégénérescence
Nibha Mishra: Harvard Medical School
Stefano Antonucci: Ulm University
Sylvie Dirrig-Grosch: Mécanismes centraux et périphériques de la neurodégénérescence
Jan Kassubek: Ulm University
Volker Rasche: Department of Internal Medicine II
Albert Ludolph: Ulm University
Anne-Laurence Boutillier: Laboratoire de Neurosciences Cognitives et Adaptatives (LNCA)
Francesco Roselli: Ulm University
Magdalini Polymenidou: University of Zurich
Clotilde Lagier-Tourenne: Harvard Medical School
Sabine Liebscher: Klinikum der Universität München, Ludwig-Maximilians-University Munich
Luc Dupuis: Mécanismes centraux et périphériques de la neurodégénérescence

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23187-9

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