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000155496 1001_ $$0P:(DE-2719)9001282$$aScekic-Zahirovic, Jelena$$b0
000155496 245__ $$aCytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects.
000155496 260__ $$a[London]$$bNature Publishing Group UK$$c2021
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000155496 520__ $$aGene 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.
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000155496 650_7 $$2NLM Chemicals$$aFUS protein, mouse
000155496 650_7 $$2NLM Chemicals$$aRNA-Binding Protein FUS
000155496 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000155496 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: metabolism
000155496 650_2 $$2MeSH$$aAnimals
000155496 650_2 $$2MeSH$$aCytoplasm: metabolism
000155496 650_2 $$2MeSH$$aFemale
000155496 650_2 $$2MeSH$$aGene Expression
000155496 650_2 $$2MeSH$$aGene Knock-In Techniques
000155496 650_2 $$2MeSH$$aMale
000155496 650_2 $$2MeSH$$aMice
000155496 650_2 $$2MeSH$$aMice, Inbred C57BL
000155496 650_2 $$2MeSH$$aMotor Neurons: metabolism
000155496 650_2 $$2MeSH$$aMutation
000155496 650_2 $$2MeSH$$aPhenotype
000155496 650_2 $$2MeSH$$aRNA-Binding Protein FUS: genetics
000155496 650_2 $$2MeSH$$aRNA-Binding Protein FUS: metabolism
000155496 650_2 $$2MeSH$$aSynapses: metabolism
000155496 650_2 $$2MeSH$$aSynaptic Transmission: physiology
000155496 7001_ $$0P:(DE-HGF)0$$aSanjuan-Ruiz, Inmaculada$$b1
000155496 7001_ $$aKan, Vanessa$$b2
000155496 7001_ $$aMegat, Salim$$b3
000155496 7001_ $$0P:(DE-HGF)0$$aDe Rossi, Pierre$$b4
000155496 7001_ $$aDieterlé, Stéphane$$b5
000155496 7001_ $$aCassel, Raphaelle$$b6
000155496 7001_ $$aJamet, Marguerite$$b7
000155496 7001_ $$0P:(DE-HGF)0$$aKessler, Pascal$$b8
000155496 7001_ $$0P:(DE-2719)2812844$$aWiesner, Diana$$b9
000155496 7001_ $$aTzeplaeff, Laura$$b10
000155496 7001_ $$aDemais, Valérie$$b11
000155496 7001_ $$aSahadevan, Sonu$$b12
000155496 7001_ $$0P:(DE-HGF)0$$aHembach, Katharina M$$b13
000155496 7001_ $$aMuller, Hans-Peter$$b14
000155496 7001_ $$aPicchiarelli, Gina$$b15
000155496 7001_ $$aMishra, Nibha$$b16
000155496 7001_ $$0P:(DE-2719)9001541$$aAntonucci, Stefano$$b17$$udzne
000155496 7001_ $$aDirrig-Grosch, Sylvie$$b18
000155496 7001_ $$0P:(DE-HGF)0$$aKassubek, Jan$$b19
000155496 7001_ $$0P:(DE-HGF)0$$aRasche, Volker$$b20
000155496 7001_ $$0P:(DE-2719)2812633$$aLudolph, Albert$$b21
000155496 7001_ $$0P:(DE-HGF)0$$aBoutillier, Anne-Laurence$$b22
000155496 7001_ $$0P:(DE-2719)2812851$$aRoselli, Francesco$$b23
000155496 7001_ $$0P:(DE-HGF)0$$aPolymenidou, Magdalini$$b24
000155496 7001_ $$0P:(DE-HGF)0$$aLagier-Tourenne, Clotilde$$b25
000155496 7001_ $$0P:(DE-2719)9000187$$aLiebscher, Sabine$$b26
000155496 7001_ $$0P:(DE-HGF)0$$aDupuis, Luc$$b27
000155496 773__ $$0PERI:(DE-600)2553671-0$$a10.1038/s41467-021-23187-9$$gVol. 12, no. 1, p. 3028$$n1$$p3028$$tNature Communications$$v12$$x2041-1723$$y2021
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