Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

Scekic‐Zahirovic, Jelena; Sanjuan-Ruiz, Inmaculada; Kan, Vanessa W. Y.; Megat, Salim; Rossi, Pierre De; Dieterlé, Stéphane; Cassel, Raphaelle; Kessler, Pascal; Wiesner, Diana; Tzeplaeff, Laura; Demais, Valérie; Müller, Hans‐Peter; Picchiarelli, Gina; Mishra, Neha; Dirrig‐Grosch, Sylvie; Kassubek, Jan; Rasche, Volker; Ludolph, Albert C.; Boutillier, Anne‐Laurence; Polymenidou, Magdalini; Lagier‐Tourenne, Clotilde; Liebscher, Sabine; Dupuis, Luc

doi:10.1101/2020.06.09.141556

Cited by 2 publications

(4 citation statements)

References 106 publications

(140 reference statements)

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“…Inhibitory synaptic defects and early behavioural phenotypes have been reported in a similar mouse carrying a truncated FUS knock-in mutation (27) and indicated a developmental role of this gene (50).…”

Section: Discussionmentioning

confidence: 88%

“…The transcriptional effect of abolishing FUS NLS has been reported from frontal cortex and spinal cord in mice, although the reported transcriptional changes were late onset and/or limited (29,35).…”

Section: Discussionmentioning

confidence: 94%

“…FUS mislocalization reportedly also caused synaptic disruptions and reduced dendrite arborization, which altered brain connections (26,27). Further studies are needed to clarify the role of FUS in the development and maintenance of brain structure and function, and in the context of neurological disease.…”

Section: Introductionmentioning

confidence: 99%

“…Recent investigations demonstrated that FUS mutation altered local mRNA translation in axons and dendrites (25,26) and that FUS is needed for correct synapse function in the brain (27). FUS mislocalisation reportedly also caused synaptic disruptions and reduced dendrite arborisation, which altered brain connections (28,29). Further studies are needed to clarify the role of FUS in the development and maintenance of brain structure and function, and in the context of neurological disease.…”

Section: Introductionmentioning

confidence: 99%

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FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Godoy-Corchuelo

Ali

Martins-Bach

et al. 2023

Preprint

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FUS (Fused in sarcoma) is a ubiquitously expressed RNA binding protein, which is mislocalized and aggregated in some forms of frontotemporal dementia (FTD), whilst mutations in FUS cause aggressive juvenile forms of amyotrophic lateral sclerosis (ALS), as in the case with the FUSDelta14 mutation. Most studies have focused on the role of FUS in motor neuron degeneration, although it is unknown whether FUS mutations affect other cell and tissue types, and the neurodevelopmental impact of FUS mutation on the nervous system is unclear. Here we studied pleiotropic phenotypes in a physiological knock-in mouse model carrying a partially humanised FUSDelta14 mutation in homozygosity. We performed RNA sequencing of six different tissues (frontal cortex, spinal cord, tibialis anterior muscle, white and brown adipose tissue and liver) and found that the genes and pathways affected were generally tissue-specific and showed few commonalities. Phenotypic assessment of homozygous FUSDelta14 mice revealed systemic metabolic alterations related to the pathway changes identified. Homozygous FUSDelta14 brains displayed significant morphological alterations including a thinner cortex, reduced neuronal number and increased gliosis, which correlated with fatal seizures in early adult life. Altogether, our data supports a wide-ranging role for FUS, and suggests that the disease aetiology of FUS mutation can include developmental and pleiotropic phenotypes.

show abstract

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Godoy-Corchuelo

Ali

Martins-Bach

et al. 2023

Preprint

View full text Add to dashboard Cite

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Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS

et al. 2021

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Mutations disrupting the nuclear localization of the RNA-binding protein FUS characterize a subset of amyotrophic lateral sclerosis patients (ALS-FUS). FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Using super-resolution imaging we determined that the localization of FUS within synapses occurs predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosomes, we identified synaptic FUS RNA targets, encoding proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a mouse model of ALS was accompanied by alterations in density and size of GABAergic synapses. mRNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term mRNA stability via binding primarily on multiple exonic sites. Our study indicates that synaptic FUS accumulation in early disease leads to synaptic impairment, potentially representing an initial trigger of neurodegeneration.

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Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

Cited by 2 publications

References 106 publications

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

FUSDelta14 mutation impairs normal brain development and causes systemic metabolic alterations

Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS

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