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Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory
Jelena Scekic-Zahirovic1, Inmaculada Sanjuan-Ruiz1, Vanessa Kan2,3
1Université de Strasbourg, Inserm, Mécanismes centraux et périphériques de la neurodégénérescence, Strasbourg, France.
Nature Communications
|May 22, 2021
Summary
Cytoplasmic mislocalization of the FUS protein causes behavioral changes like hyperactivity in mice. This suggests FUS protein issues may impact more than just motor neurons in neurodegenerative diseases.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS (Fused in Sarcoma) are linked to severe amyotrophic lateral sclerosis (ALS).
- Cytoplasmic accumulation of FUS is also observed in other diseases, but its consequences remain unclear.
Purpose of the Study:
- To investigate the behavioral and neurological consequences of cytoplasmic FUS mislocalization in vivo.
- To elucidate the molecular mechanisms underlying FUS-driven neurotoxicity.
Main Methods:
- Utilized knock-in mouse models with FUS mislocalization.
- Performed in vivo electrophysiological recordings in the frontal cortex.
- Conducted synaptic ultrastructural and morphological analyses.
- Assessed synaptosomal FUS and RNA target levels.
Main Results:
- Cytoplasmic FUS mislocalization induced behavioral abnormalities, including locomotor hyperactivity and altered social interactions, without significant neuronal loss.
- Progressive increases in neuronal activity were observed in the frontal cortex of Fus knock-in mice.
- Synaptic deficits, particularly in inhibitory synapses, were associated with increased FUS and RNA targets in synaptosomes.
- These synaptic changes correlated with altered synaptic gene expression and increased frontal cortex neuronal activity.
Conclusions:
- Cytoplasmic FUS mislocalization drives synaptic deficits and subsequent neuronal hyperactivity, leading to behavioral phenotypes.
- FUS mislocalization may contribute to neurodegeneration beyond motor neuron impairment in ALS.
- These findings are potentially relevant for other neurodegenerative diseases involving FUS mislocalization.
