TY  - JOUR
AU  - Scekic-Zahirovic, Jelena
AU  - Sanjuan-Ruiz, Inmaculada
AU  - Kan, Vanessa
AU  - Megat, Salim
AU  - De Rossi, Pierre
AU  - Dieterlé, Stéphane
AU  - Cassel, Raphaelle
AU  - Jamet, Marguerite
AU  - Kessler, Pascal
AU  - Wiesner, Diana
AU  - Tzeplaeff, Laura
AU  - Demais, Valérie
AU  - Sahadevan, Sonu
AU  - Hembach, Katharina M
AU  - Muller, Hans-Peter
AU  - Picchiarelli, Gina
AU  - Mishra, Nibha
AU  - Antonucci, Stefano
AU  - Dirrig-Grosch, Sylvie
AU  - Kassubek, Jan
AU  - Rasche, Volker
AU  - Ludolph, Albert
AU  - Boutillier, Anne-Laurence
AU  - Roselli, Francesco
AU  - Polymenidou, Magdalini
AU  - Lagier-Tourenne, Clotilde
AU  - Liebscher, Sabine
AU  - Dupuis, Luc
TI  - Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.
JO  - Nature Communications
VL  - 12
IS  - 1
SN  - 2041-1723
CY  - [London]
PB  - Nature Publishing Group UK
M1  - DZNE-2021-00692
SP  - 3028
PY  - 2021
AB  - 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.
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Animals
KW  - Cytoplasm: metabolism
KW  - Female
KW  - Gene Expression
KW  - Gene Knock-In Techniques
KW  - Male
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Motor Neurons: metabolism
KW  - Mutation
KW  - Phenotype
KW  - RNA-Binding Protein FUS: genetics
KW  - RNA-Binding Protein FUS: metabolism
KW  - Synapses: metabolism
KW  - Synaptic Transmission: physiology
KW  - FUS protein, mouse (NLM Chemicals)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:34021132
C2  - pmc:PMC8140148
DO  - DOI:10.1038/s41467-021-23187-9
UR  - https://pub.dzne.de/record/155496
ER  -