Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Ajmone‐Cat, Maria Antonietta; Onori, Angela; Toselli, Camilla; Stronati, Eleonora; Morlando, Mariangela; Bozzoni, Irene; Monni, Emanuela; Kokaia, Zaal; Lupo, Giuseppe; Minghetti, Luisa; Biagioni, Stefano; Cacci, Emanuele

doi:10.1038/s41598-019-41040-4

Cited by 36 publications

(34 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, mutations in FUS 3’UTR were described in ALS patients and linked to an increased level of FUS mRNA and protein (Zou et al , 2012; Sabatelli et al , 2013; Dini Modigliani et al , 2014). Surprisingly, over‐expression of wild‐type FUS provokes an aggressive ALS phenotype in mice and fruit flies, in accordance with findings in yeast and mammalian cells (Ju et al , 2011; Chen et al , 2011; Miguel et al , 2012; Ajmone‐Cat et al , 2019; Ling et al , 2019). The mechanism of the wild‐type or ALS‐linked mutated FUS toxicity remains unclear (Deng et al , 2014; Taylor et al , 2016; Nolan et al , 2016).…”

Section: Introductionsupporting

confidence: 84%

The FUS gene is dual‐coding with both proteins contributing to FUS ‐mediated toxicity

et al. 2020

View full text Add to dashboard Cite

Novel functional coding sequences (altORFs) are camouflaged within annotated ones (CDS) in a different reading frame. We show here that an altORF is nested in the FUS CDS, encoding a conserved 170 amino acid protein, altFUS. AltFUS is endogenously expressed in human tissues, notably in the motor cortex and motor neurons. Over-expression of wild-type FUS and/or amyotrophic lateral sclerosis-linked FUS mutants is known to trigger toxic mechanisms in different models. These include inhibition of autophagy, loss of mitochondrial potential and accumulation of cytoplasmic aggregates. We find that altFUS, not FUS, is responsible for the inhibition of autophagy, and pivotal in mitochondrial potential loss and accumulation of cytoplasmic aggregates. Suppression of altFUS expression in a Drosophila model of FUS-related toxicity protects against neurodegeneration. Some mutations found in ALS patients are overlooked because of their synonymous effect on the FUS protein. Yet, we show they exert a deleterious effect causing missense mutations in the overlapping altFUS protein. These findings demonstrate that FUS is a bicistronic gene and suggests that both proteins, FUS and altFUS, cooperate in toxic mechanisms.

show abstract

Section: Introductionsupporting

confidence: 84%

The FUS gene is dual‐coding with both proteins contributing to FUS ‐mediated toxicity

et al. 2020

View full text Add to dashboard Cite

show abstract

“…The FTLD-FUS group had a low burden of all microglial phenotypes, with limited activation, in all regions. ALS mouse models expressing wild-type FUS display a pro-inflammatory microglial phenotype and excessive release of inflammatory cytokines [60]. However, all FTLD-FUS cases were previously diagnosed as aFTLD-U, which tend to have more severe pathology in the hippocampus and subcortical grey and brainstem nuclei, with less cortical and subcortical white matter involvement [46].…”

Section: Discussionmentioning

confidence: 99%

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

Woollacott

Toomey

Strand

et al. 2020

J Neuroinflammation

View full text Add to dashboard Cite

Background: Microglial dysfunction is implicated in frontotemporal lobar degeneration (FTLD). Although studies have reported excessive microglial activation or senescence (dystrophy) in Alzheimer's disease (AD), few have explored this in FTLD. We examined regional patterns of microglial burden, activation and dystrophy in sporadic and genetic FTLD, sporadic AD and controls. Methods: Immunohistochemistry was performed in frontal and temporal grey and white matter from 50 pathologically confirmed FTLD cases (31 sporadic, 19 genetic: 20 FTLD-tau, 26 FTLD-TDP, four FTLD-FUS), five AD cases and five controls, using markers to detect phagocytic (CD68-positive) and antigen-presenting (CR3/43positive) microglia, and microglia in general (Iba1-positive). Microglial burden and activation (morphology) were assessed quantitatively for each microglial phenotype. Iba1-positive microglia were assessed semi-quantitatively for dystrophy severity and qualitatively for rod-shaped and hypertrophic morphology. Microglia were compared in each region between FTLD, AD and controls, and between different pathological subtypes of FTLD, including its main subtypes (FTLD-tau, FTLD-TDP, FTLD-FUS), and subtypes of FTLD-tau, FTLD-TDP and genetic FTLD. Microglia were also compared between grey and white matter within each lobe for each group. Results: There was a higher burden of phagocytic and antigen-presenting microglia in FTLD and AD cases than controls, but activation was often not increased. Burden was generally higher in white matter than grey matter, but activation was greater in grey matter. However, microglia varied regionally according to FTLD subtype and disease mechanism. Dystrophy was more severe in FTLD and AD than controls, and more severe in white than grey matter, but this also varied regionally and was particularly extensive in FTLD due to progranulin (GRN) mutations. Presence of rod-shaped and hypertrophic microglia also varied by FTLD subtype.

show abstract

“…In addition to controlling the synthesis of ECM components, FUS seems to play a role in inflammation. Overexpression of FUS in murine and human astrocytes leads to up-regulation of several genes implicated in inflammatory responses, including CD68, IL-6, and Csf2, to name a few ( Ajmone-Cat et al, 2019 ). Analysis of the promoters of these reported genes revealed the presence of FUS-responsive elements in most of them ( Table S1 ).…”

Section: Discussionmentioning

confidence: 99%

EGF receptor–mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling

Chiusa

Zienkiewicz

et al. 2020

Journal of Cell Biology

View full text Add to dashboard Cite

Excessive accumulation of collagen leads to fibrosis. Integrin α1β1 (Itgα1β1) prevents kidney fibrosis by reducing collagen production through inhibition of the EGF receptor (EGFR) that phosphorylates cytoplasmic and nuclear proteins. To elucidate how the Itgα1β1/EGFR axis controls collagen synthesis, we analyzed the levels of nuclear tyrosine phosphorylated proteins in WT and Itgα1-null kidney cells. We show that the phosphorylation of the RNA-DNA binding protein fused in sarcoma (FUS) is higher in Itgα1-null cells. FUS contains EGFR-targeted phosphorylation sites and, in Itgα1-null cells, activated EGFR promotes FUS phosphorylation and nuclear translocation. Nuclear FUS binds to the collagen IV promoter, commencing gene transcription that is reduced by inhibiting EGFR, down-regulating FUS, or expressing FUS mutated in the EGFR-targeted phosphorylation sites. Finally, a cell-penetrating peptide that inhibits FUS nuclear translocation reduces FUS nuclear content and collagen IV transcription. Thus, EGFR-mediated FUS phosphorylation regulates FUS nuclear translocation and transcription of a major profibrotic collagen gene. Targeting FUS nuclear translocation offers a new antifibrotic therapy.

show abstract

Increased FUS levels in astrocytes leads to astrocyte and microglia activation and neuronal death

Cited by 36 publications

References 75 publications

The FUS gene is dual‐coding with both proteins contributing to FUS ‐mediated toxicity

The FUS gene is dual‐coding with both proteins contributing to FUS ‐mediated toxicity

Microglial burden, activation and dystrophy patterns in frontotemporal lobar degeneration

EGF receptor–mediated FUS phosphorylation promotes its nuclear translocation and fibrotic signaling

Contact Info

Product

Resources

About