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

نویسندگان

چکیده

Abstract Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation is also observed in other diseases, with unknown consequences. Here, we show that drives behavioral abnormalities knock-in mice, including locomotor hyperactivity and alterations social interactions, absence widespread neuronal loss. Mechanistically, identified a progressive increase activity frontal cortex Fus mice vivo, associated altered synaptic gene expression. Synaptic ultrastructural morphological defects were more pronounced inhibitory than excitatory synapses increased synaptosomal levels its RNA targets. Thus, triggers deficits, which leading related phenotypes. These results indicate may trigger deleterious phenotypes beyond motor neuron impairment ALS, likely relevant for neurodegenerative diseases characterized by mislocalization.

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ژورنال

عنوان ژورنال: Nature Communications

سال: 2021

ISSN: ['2041-1723']

DOI: https://doi.org/10.1038/s41467-021-23187-9