Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-23187-9
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Funding
- Agence Nationale de la Recherche [ANR-16-CE92-0031, ANR-16-CE16-0015, ANR-19-CE17-0016]
- Fondation pour la recherche medicale (FRM) [DEQ20180339179]
- Axa Research Funds (rare diseases award 2019)
- Fondation Thierry Latran
- Radala Foundation
- MNDA [Dupuis/Apr16/852-791]
- ALSA [2235, 3209, 8075]
- Target ALS
- NINDS/NIH [R01-NS108769]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy [390857198, 431995586, 443642953, 446067541]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under the SonderForschungsBereich (SFB) 1149/2 [251293561]
- Emmy Noether Programme
- Deutsche Gesellschaft fur Muskelkranke e.V.
- Graduate School for Systemic Neurosciences GSN-LMU
- Araminta Broch-Healey Endowed Chair in ALS
- ARSLA
- Region Grand Est (France)
- Agence Nationale de la Recherche (ANR) [ANR-16-CE92-0031] Funding Source: Agence Nationale de la Recherche (ANR)
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Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
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. Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.
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