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FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

ABSTRACT: Pathological FUS inclusions are found in 10% of patients with frontotemporal dementia (FTD) and those with amyotrophic lateral sclerosis (ALS) carrying FUS mutations. Current work indicates that FUS mutations may incur gain-of-toxic functions to drive ALS pathogenesis. However, how FUS dysfunction may affect cognition remains elusive. Using a mouse model expressing wild-type human FUS mimicking the endogenous expression pattern and level within the central nervous system, we found that they developed hippocampus-mediated cognitive deficits accompanied by an age-dependent reduction in spine density and long-term potentiation (LTP) in their hippocampus. However, there were no apparent FUS aggregates, nuclear envelope defects and cytosolic FUS accumulation. These suggest that these proposed pathogenic mechanisms may not be the underlying causes for the observed cognitive deficits. Unbiased transcriptomic analysis identified expression changes in a small set of genes with preferential expression in the neurons and oligodendrocyte lineage cells. Of these, we focused on Sema5a, a gene involved in axon guidance, spine dynamics, Parkinson’s disease and autism spectrum disorders. Critically, FUS binds directly to Sema5a mRNA and regulates Sema5a expression in a FUS-dose-dependent manner. Taken together, our data suggest that FUS-driven Sema5a deregulation may underlie the cognitive deficits in FUS transgenic mice.

ORGANISM(S): Mus musculus

PROVIDER: GSE135075 | GEO | 2020/07/30

REPOSITORIES: GEO

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Dysfunctions in nonsense-mediated decay, protein homeostasis, OXPHOS function, and brain connectivity in ALS-FUS mice with cognitive deficits

Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent two ends of the same disease spectrum of adult-onset neurodegenerative diseases that affect the spinal cord and neocortex, respectively. Multiple common genetic loci such as FUS (fused-in-sarcoma) have been identified to have a role in ALS and FTD aetiology. Current work indicates that FUS mutations incur gain-of-toxic functions to drive ALS pathogenesis. However, how the disease-linked mutations of FUS may affect cognition remains elusive. Using a mouse model expressing an ALS-linked FUS mutation (R514G) that mimics mouse endogenous expression patterns, we found that FUS proteins showed an age-dependent accumulation despite the fact that the R514G protein was able to down-regulate mouse FUS mRNA during aging. Furthermore, these mice developed cognitive deficits accompanied by a reduction in spine density and long-term potentiation (LTP) within the hippocampus. At the physiological expression level, mutant FUS is distributed in the nucleus and cytosol without apparent FUS aggregates or nuclear envelope defects. Unbiased transcriptomic analysis reveals downregulated genes clustered in pathways involved in protein homeostasis, including components of ribosomal proteins and ubiquitin-proteasome pathway, and mitochondrial functions. Furthermore, using in vivo functional imaging, we uncovered that R514G mice exhibited widespread reduction in cortical volumes, yet enhanced functional connectivity between hippocampus, basal ganglia and neocortex. Taken together, our data suggest that disease-linked mutation in FUS may lead to change in proteostasis and dysfunctional mitochondria, which in turns affect brain structure and connectivity resulting in cognitive deficits.

2021-01-11 | GSE157713 | GEO

FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

Project description:FUS-mediated dysregulation of Sema5a, an autism-related gene, in FUS mice with hippocampus-dependent cognitive deficits

| PRJNA557350 | ENA

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (CLIP-seq)

Project description:FUS is a primarily nuclear RNA-binding protein with important roles in RNA processing and transport. FUS mutations disrupting its nuclear localization characterize a subset of amyotrophic lateral sclerosis (ALS-FUS) patients, through an unidentified pathological mechanism. FUS regulates nuclear RNA, but its role at the synapse is poorly understood. Here, we used super-resolution imaging to determine the physiological localization of extranuclear, neuronal FUS and found it predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosome preparations, we identified synaptic RNA targets of FUS that are associated with synapse organization and plasticity. Synaptic FUS was significantly increased in a knock-in mouse model of ALS-FUS, at presymptomatic stages. Despite apparently unaltered synaptic organization, RNA-seq of synaptoneurosomes highlighted age-dependent dysregulation of glutamatergic and GABAergic synapses. Our study indicates that FUS relocalization to the synapse in early stages of ALS-FUS results in synaptic impairment, potentially representing an initial trigger of neurodegeneration.

2021-03-05 | E-MTAB-9211 | biostudies-arrayexpress

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (RNA-seq)

2021-03-05 | E-MTAB-9212 | biostudies-arrayexpress

Mutant FUS triggers age-dependent synaptic impairment in presymptomatic ALS-FUS mice (RNA-seq part2)

2021-03-05 | E-MTAB-10104 | biostudies-arrayexpress

Identification of in vivo, conserved, FUS RNA binding sites and the impact of FUS on the neuronal transcriptome

Project description:FUS, an RNA binding protein was recently implicated in Amyotrophic Lateral Sclerosis (ALS). ALS is a fatal neurodegenerative disease. We report the identification of the conserved neuronal RNA targets of FUS and the assessment of the impact of FUS depletion on the neuronal transcriptome. We identified that FUS regulates splicing of conserved intron containing transcripts. FUS retains or excludes the conserved intron by binding to them. Identification of FUS neuronal targets using normal human brain samples and mouse neurons

2013-01-25 | E-GEOD-43308 | biostudies-arrayexpress

SynGAP variant from Japanese ALS cohort alters the recruitment of RNA binding proteins

Project description:FUS is one of the pathogenic RNA-binding proteins for amyotrophic lateral sclerosis (ALS). We previously reported that FUS stabilized SynGAP mRNA at its 3’UTR and maintained spine maturation and cognitive function in mice. To elucidate whether this mechanism could be pathogenic for ALS, we identified SynGAP 3’UTR variant at the binding site of FUS, different from that in mice, from a multicenter cohort in Japan. Human induced pluripotent stem cells (hiPSC)-derived motor neurons with SynGAP variant showed spine abnormality with aberrant SynGAP splicing. To evaluate how SynGAP variant altered the access of RNA binding proteins to SynGAP 3'UTR, we performed pull down assay by using biotinylated RNA probes with or without the variant.

2023-03-11 | PXD026586 | Pride

Identification of in vivo, conserved, FUS RNA binding sites and the impact of FUS on the neuronal transcriptome

2013-01-25 | GSE43308 | GEO

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

Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare NGS-derived frontal cortex transcriptome profiling (RNA-seq) from control and a mouse of ALS-FUS. 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 profound increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo. Importantly, RNAseq analysis suggested involvement of defects in inhibitory neurons, that was confirmed by ultrastructural and morphological defects of inhibitory synapses and increased synaptosomal levels of mRNAs involved in inhibitory neurotransmission. Thus, cytoplasmic FUS triggers inhibitory synaptic deficits, leading to increased neuronal activity and behavioral phenotypes. FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, but also in other neurodegenerative diseases with FUS mislocalization.

2021-02-12 | GSE166615 | GEO

Synaptic accumulation of FUS triggers early misregulation of synaptic RNAs in ALS-FUS mice

Project description: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 knock-in mouse model of ALS-FUS 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.

2021-05-05 | PXD024075 | Pride

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