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

Jelena Scekic‐Zahirovic ,Valérie Demais,Albert C Ludolph ,Jan Kassubek,Gina Picchiarelli,Raphaelle Cassel,Anne‐Laurence Boutillier ,Volker Rasche,Francesco Roselli,Stéphane Dieterle ,Magdalini Polymenidou,Clotilde Lagier‐Tourenne ,Sonu Sahadevan,Pascal Kessler,Laura Tzeplaeff,Diana Wiesner,Hans‐Peter Müller ,Sabine Liebscher,Pierre De Rossi,Neha Mishra ,Vanessa W Y Kan ,Stefano Antonucci,Sylvie Dirrig‐Grosch ,Inmaculada Sanjuan-Ruiz,Katharina Hembach ,Marguerite Jamet,Salim Megat,Luc Dupuis

doi:10.1038/s41467-021-23187-9

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.

Highlights

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein Fused in Sarcoma gene (FUS) lead to severe forms of amyotrophic lateral sclerosis (ALS)
Since FUS mislocalization and aggregation are observed in patients with various neurodegenerative diseases, we hypothesized that partial FUS cytoplasmic mislocalization in FusΔNLS/+ mice could be sufficient to cause a number of behavioral phenotypes
We show that knock-in mice with cytoplasmic accumulation of FUS display widespread behavioral alterations, beyond motor symptoms

Summary

Introduction

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). 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 for other neurodegenerative diseases characterized by FUS mislocalization. Mutations in the Fused in Sarcoma gene (FUS), encoding an RNA-binding protein from the FET family[4,5], are associated with the most severe forms of ALS6,7, clinically presenting with a very early onset and rapid disease progression[8,9]. Heterozygous Fus knock-in mice, which carry one mutant allele leading to cytoplasmic and not nuclear localization of FUS, only show marginal loss of nuclear FUS due to compensatory overexpression[10,41]

Methods

Results

Conclusion