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M6A reduction relieves FUS-associated ALS granules [RNA-Seq]

ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration1. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by mutant protein aggregation, among which the RNA binding protein FUS2. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished as a consequence of the m6A writer METTL3 knock-down. These effects were obtained observed both in neuronal cell lines and in iPSC-derived human motor neurons expressing mutant FUS. Importantly, stress granules formed in mutant conditionswhen mutant FUS is expressed/ALS condition showed a distinctive transcriptome with respect to control cells; interestingly, after METTL3 downregulation, it reverted to similar to control. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, a well characterized inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

ORGANISM(S): Homo sapiens

PROVIDER: GSE242766 | GEO | 2024/05/06

REPOSITORIES: GEO

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M6A reduction relieves FUS-associated ALS granules [CLIP-seq]

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by mutant protein aggregation, among which the RNA binding protein FUS. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished as a consequence of the m6A writer METTL3 knock-down. These effects were obtained observed both in neuronal cell lines and in iPSC-derived human motor neurons expressing mutant FUS. Importantly, stress granules formed in mutant conditionswhen mutant FUS is expressed/ALS condition showed a distinctive transcriptome with respect to control cells; interestingly, after METTL3 downregulation, it reverted to similar to control. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, a well characterized inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

2024-05-06 | GSE256070 | GEO

M6A reduction relieves FUS-associated ALS granules [m6A-IP]

Project description:Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease due to gradual motorneurons (MN) degeneration1. Among the processes associated to ALS pathogenesis, there is the formation of cytoplasmic inclusions produced by mutant protein aggregation, among which the RNA binding protein FUS. In this work we show that such inclusions are significantly reduced in number and dissolve faster when the RNA m6A content is diminished as a consequence of the m6A writer METTL3 knock-down. These effects were obtained observed both in neuronal cell lines and in iPSC-derived human motor neurons expressing mutant FUS. Importantly, stress granules formed in mutant conditionswhen mutant FUS is expressed/ALS condition showed a distinctive transcriptome with respect to control cells; interestingly, after METTL3 downregulation, it reverted to similar to control. Finally, we show that FUS inclusions are reduced also in patient-derived fibroblasts treated with STM-2457, a well characterized inhibitor of METTL3 activity, paving the way for its possible use for counteracting aggregate formation in ALS.

2024-05-06 | GSE242770 | GEO

Drosha-dependent microRNAs modulate FUS-mediated neurodegeneration in vivo

Project description:Mutations in Fused in Sarcoma (FUS) gene cause the familial and progressive form of amyotrophic lateral sclerosis (ALS). FUS is a nuclear RNA-binding protein involved in RNA processing and the biogenesis of a specific set of microRNAs. Here we report that Drosha and two previously uncharacterized Drosha-dependent miRNAs are strong modulators of FUS expression and prevent the cytoplasmic segregation of insoluble mutant FUS in vivo. We demonstrate that depletion of Drosha mitigates FUS-mediated degeneration, survival, and motor defects in Drosophila. Mutant FUS strongly interacts with Drosha and causes its cytoplasmic mis-localization into the insoluble FUS inclusions. Reduction in Drosha levels increases the solubility of mutant FUS. Interestingly, we found two Drosha dependent microRNAs, miR-378i and miR-6832-5p, which differentially regulate the expression, solubility, and cytoplasmic aggregation of mutant FUS in iPSC neurons and mammalian cells. More importantly, we report different modes of action of these miRNAs against mutant FUS. Whereas miR-378i may regulate mutant FUS inclusions by preventing G3BP-mediated stress granule formation, miR-6832-5p may affect FUS expression via other proteins or pathways. Overall, our research reveals a possible association between ALS-linked FUS mutations and the Drosha-dependent miRNA regulatory circuit, as well as a useful perspective on potential ALS treatment via microRNAs.

2023-09-09 | GSE242360 | GEO

M6A reduction relieves FUS-associated ALS granules

Project description:M6A reduction relieves FUS-associated ALS granules

| PRJNA1014474 | ENA

M6A reduction relieves FUS-associated ALS granules [m6A-IP]

Project description:M6A reduction relieves FUS-associated ALS granules [m6A-IP]

| PRJNA1014475 | ENA

M6A reduction relieves FUS-associated ALS granules [RNA-Seq]

Project description:M6A reduction relieves FUS-associated ALS granules [RNA-Seq]

| PRJNA1014473 | ENA

M6A reduction relieves FUS-associated ALS granules [CLIP-seq]

Project description:M6A reduction relieves FUS-associated ALS granules [CLIP-seq]

| PRJNA1077990 | ENA

Activation of polo-like kinase 1 expression in spinal motor neurons as vulnerability factor of spinal motor neurons in FUS- and other fALS

Project description:FUS ALS seems to preferentially affect sMNs, and cognitive dysfunction in FUS ALS is rare. Considering this, we wanted to analyze if cortical neurons behave differently than spinal motor neurons in response to FUS mutations. For this, we used cortical neurons derived from isogenic human induced pluripotent stem cells (hiPSCs) in which either WT or NLS mutant FUS P525L was tagged with eGFP using CRISPR/Cas9 and systematically compared them to sMNs of the identical iPSCs. Phenotypically, mutant FUS cortical neurons showed less impairment of FUS recruitment to DNA damage sites compared to mutant sMNs and less signs of DNA damage, which were similarly found in post mortem tissue. To advance our understanding of finding different molecular mechanisms and pathways related to FUS mutations in ALS disease, we have performed RNA sequencing of FUS ALS cortical and spinal motor neurons and our results revealed basic differences in their transcriptomes. Alternative splicing events in spinal motor neurons were different from cortical neurons also pointing towards DNA damage in FUS ALS.

2024-08-27 | GSE272827 | GEO

DDX17 is involved in DNA damage repair and modifies FUS toxicity in an RGG-domain dependent manner

Project description:Mutations in the RNA binding protein, Fused in Sarcoma (FUS), lead to amyotrophic lateral sclerosis (ALS), the most frequent form of motor neuron disease. Cytoplasmic aggregation and defective DNA repair machinery are etiologically linked to mutant FUS-associated ALS. Although FUS is involved in numerous aspects of RNA processing, little is understood about the pathophysiological mechanisms of mutant FUS. Here, we employed RNA-sequencing technology in Drosophila brains expressing FUS to identify significantly altered genes and pathways involved in FUS-mediated neurodegeneration.

2021-05-05 | GSE173838 | GEO

ALS-associated FUS mutation reshapes the RNA and protein composition and dynamic of Stress Granules.

Project description:Stress Granules (SG) formation is a cellular protection mechanism in harmful conditions, constituting a storage for untranslated mRNAs and RNA-binding proteins (RBPs); however, these condensates can turn into pathological aggregates, that in neurons are related to the onset of neurodegenerative diseases, like Amyotrophic Lateral Sclerosis (ALS). Mutations in the RBP FUS, leading to its cytoplasmic mis-localization, are causatively linked to ALS, since they mediate its accumulation in SGs, triggering their transition towards cytotoxic inclusions. Here, we describe the SG transcriptome in a neural context and compare with datasets from other systems, identifying both common rules and diversifying characteristics for SG recruitment of transcripts. We demonstrate that SG dynamics and RNA content are strongly modified by the incorporation of aberrantly localized mutant FUS, switching to a more unstructured, AU-rich SG transcriptome and losing a wide population of GC-rich, structured RNAs. We show that these alterations mainly depend on mutant FUS which favors the SG incorporation of its protein interactors and in turn of their target RNAs. Our data give a comprehensive view of the molecular differences between physiological and pathological SG in ALS conditions, showing how a single mutation is sufficient to impact the RNA and protein population of these condensates.

2024-12-06 | GSE244751 | GEO

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