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@ARTICLE{ScekicZahirovic:155496,
author = {Scekic-Zahirovic, Jelena and Sanjuan-Ruiz, Inmaculada and
Kan, Vanessa and Megat, Salim and De Rossi, Pierre and
Dieterlé, Stéphane and Cassel, Raphaelle and Jamet,
Marguerite and Kessler, Pascal and Wiesner, Diana and
Tzeplaeff, Laura and Demais, Valérie and Sahadevan, Sonu
and Hembach, Katharina M and Muller, Hans-Peter and
Picchiarelli, Gina and Mishra, Nibha and Antonucci, Stefano
and Dirrig-Grosch, Sylvie and Kassubek, Jan and Rasche,
Volker and Ludolph, Albert and Boutillier, Anne-Laurence and
Roselli, Francesco and Polymenidou, Magdalini and
Lagier-Tourenne, Clotilde and Liebscher, Sabine and Dupuis,
Luc},
title = {{C}ytoplasmic {FUS} triggers early behavioral alterations
linked to cortical neuronal hyperactivity and inhibitory
synaptic defects.},
journal = {Nature Communications},
volume = {12},
number = {1},
issn = {2041-1723},
address = {[London]},
publisher = {Nature Publishing Group UK},
reportid = {DZNE-2021-00692},
pages = {3028},
year = {2021},
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 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.},
keywords = {Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
Lateral Sclerosis: metabolism / Animals / Cytoplasm:
metabolism / Female / Gene Expression / Gene Knock-In
Techniques / Male / Mice / Mice, Inbred C57BL / Motor
Neurons: metabolism / Mutation / Phenotype / RNA-Binding
Protein FUS: genetics / RNA-Binding Protein FUS: metabolism
/ Synapses: metabolism / Synaptic Transmission: physiology /
FUS protein, mouse (NLM Chemicals) / RNA-Binding Protein FUS
(NLM Chemicals)},
cin = {AG Roselli / Clinical Study Center Ulm},
ddc = {500},
cid = {I:(DE-2719)1910001 / I:(DE-2719)5000077},
pnm = {353 - Clinical and Health Care Research (POF4-353) / 352 -
Disease Mechanisms (POF4-352)},
pid = {G:(DE-HGF)POF4-353 / G:(DE-HGF)POF4-352},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:34021132},
pmc = {pmc:PMC8140148},
doi = {10.1038/s41467-021-23187-9},
url = {https://pub.dzne.de/record/155496},
}