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 profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵* shared first authors
Funding This work was funded by Agence Nationale de la Recherche (ANR-16-CE92-0031 to ALB and LD, ANR-16-CE16-0015 to LD), by Fondation pour la recherche médicale (FRM, DEQ20180339179), Axa Research Funds (rare diseases award 2019, to LD), Fondation Thierry Latran (HypmotALS, to LD), MNDA (Dupuis/Apr16/852-791 to LD), ALSA (2235, 3209 and 8075 to LD and CLT), Target ALS (to CLT), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology - EXC 2145 SyNergy - ID 390857198 (SL), the DFG, Emmy Noether Programme (SL), the Deutsche Gesellschaft für Muskelkranke (SL) and the Graduate School for Systemic Neurosciences GSN-LMU (ZG, VK). CLT is the recipient of the Araminta Broch-Healey Endowed Chair in ALS. The collaborative work between LD and MP laboratories was funded by ARSLA (2016). ISR was funded by the Région Grand Est (France).