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A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats

ABSTRACT: Purpose: Compare parental NSC34 cells with NSC34 PR20-resistant clones Methods: NSC-34 cell cultures were treated with PR20, a peptide that contains 20 copies of Proline-Arginine aminoacids, for two weeks. mRNA profiles of resistant clones were generated by RNAseq. Sequencing reads were aligned and analyzed for differential gene expression. Results: NSC34 clones that gained spontaneous resistance to PR20 present a higher levels of translation than parental cells. Gene Set Enrichment Analysis (GSEA) of this dataset revealed an overall upregulation of factors from the “mTORC1 signaling” hallmark

ORGANISM(S): Mus musculus

PROVIDER: GSE110596 | GEO | 2021/02/14

REPOSITORIES: GEO

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A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats [drug treatment]

Project description:Purpose: Compare the effect of PR20 alone or together with PFI or NaPhen Methods: NSC-34 cells are wildtype in the non-coding hexanucleotide repeat status of C9orf72. NSC-34 cell cultures were treated with PR20, PFI or NaPhen alone for 48 hours, or in combination (48 hours with PR20 and the last 24 hours with PFI or NaPhen). mRNA profiles of the different conditions were generated by RNAseq. Sequencing reads were aligned and analyzed for differential gene expression. Results: The analysis reveals that the transcriptional changes induced by PR20 are alleviated by the treatment with PFI or NaPhen.

2021-06-26 | GSE116392 | GEO

A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats

Project description:A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats

| PRJNA434079 | ENA

Phase Separation of C9orf72 Dipeptide Repeats Perturbs Stress Granule Dynamics.

Project description:Liquid-liquid phase separation (LLPS) of RNA-binding proteins plays an important role in the formation of multiple membrane-less organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a cornerstone of ALS/FTLD pathogenesis. Polar residues (tyrosine and glutamine) have been previously demonstrated to be critical for phase separation of ALS-linked stress granule proteins. We now identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. Expression of arginine-rich DPRs in cells induced spontaneous stress granule assembly that required both eIF2? phosphorylation and G3BP. Together with recent reports showing that DPRs affect nucleocytoplasmic transport, our results point to an important role for arginine-rich DPRs in the pathogenesis of C9orf72 ALS/FTLD.

| S-EPMC5364369 | biostudies-literature

Phase separation of C9orf72 dipeptide repeats perturbs stress granule metabolism

Project description:Liquid-liquid phase separation (LLPS) of RNA binding proteins underlies the formation of multiple membraneless organelles involved in RNA metabolism, including stress granules. Defects in stress granule homeostasis constitute a corner stone of ALS/FTLD pathogenesis. Phase separation of ALS-linked stress granule proteins has been shown to rely on hydrophobic interactions. Here we identify an active role for arginine-rich domains in these phase separations. Moreover, arginine-rich dipeptide repeats (DPRs) derived from C9orf72 hexanucleotide repeat expansions similarly undergo LLPS, and induce phase separation of a large set of proteins involved in RNA and stress granule metabolism. In the present proteomics experiment, we wondered which cellular proteins could interact with synthetic PR30 peptide. We took soluble HeLa cell lysate, to which we added increasing concentrations of PR30. The PR30 peptide spontaneously demixed, and could be separated from the solution by gentle centrifugation. Unexpectedly, the resulting pellet was largely resistant to washing steps, suggesting that PR induced the precipitation of different cellular proteins to the insoluble fraction. To see whether weak interactions could still be involved in the process, we also performed mild crosslinking with paraformaldehyde. Mass-spectroscopy (MS) analysis on both crosslinked and uncrosslinked samples identified 874 proteins that were detected and quantified in both conditions.

2017-04-26 | PXD005509 | Pride

A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats [drug treatment]

Project description:A chemical screen identifies compounds limiting the toxicity of C9ORF72 dipeptide repeats [drug treatment]

| PRJNA478380 | ENA

C9orf72 proline-arginine dipeptide repeats disrupt the proteasome and perturb proteolytic activities.

Project description:The hexanucleotide G4C2 repeat expansion in C9orf72 is the most frequent genetic cause of familial amyotrophic lateral sclerosis (ALS). Aberrant translation of this hexanucleotide sequence leads to production of 5 dipeptide repeats (DPRs). One of these DPRs is proline-arginine (polyPR), which is found in C9orf72-expanded ALS (C9ALS) patient brain tissue and is neurotoxic across multiple model systems. PolyPR was previously reported to bind and impair proteasomes in vitro. Nevertheless, the clinical relevance of the polyPR-proteasome interaction and its functional consequences in vivo are yet to be established. Here, we aim to confirm and functionally characterize polyPR-induced impairment of proteolysis in C9ALS patient tissue and an in vivo model system. Confocal microscopy and immunofluorescence studies on both human and Drosophila melanogaster brain tissues revealed sequestration of proteasomes by polyPR into inclusion-like bodies. Co-immunoprecipitation in D. melanogaster showed that polyPR strongly binds to the proteasome. In vivo, functional evidence for proteasome impairment is further shown by the accumulation of ubiquitinated proteins along with lysosomal accumulation and hyper-acidification, which can be rescued by a small-molecule proteasomal enhancer. Together, we provide the first clinical report of polyPR-proteasome interactions and offer in vivo evidence proposing polyPR-induced proteolytic dysfunction as a pathogenic mechanism in C9ALS.

| S-EPMC10587997 | biostudies-literature

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression.

Project description:Expansion of an intronic (GGGGCC)n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

| S-EPMC7335171 | biostudies-literature

C9orf72 Poly(PR) Dipeptide Repeats Disturb Biomolecular Phase Separation and Disrupt Nucleolar Function.

Project description:Repeat expansion in the C9orf72 gene is the most common cause of the neurodegenerative disorder amyotrophic lateral sclerosis (C9-ALS) and is linked to the unconventional translation of five dipeptide-repeat polypeptides (DPRs). The two enriched in arginine, poly(GR) and poly(PR), infiltrate liquid-like nucleoli, co-localize with the nucleolar protein nucleophosmin (NPM1), and alter the phase separation behavior of NPM1 in vitro. Here, we show that poly(PR) DPRs bind tightly to a long acidic tract within the intrinsically disordered region of NPM1, altering its phase separation with nucleolar partners to the extreme of forming large, soluble complexes that cause droplet dissolution in vitro. In cells, poly(PR) DPRs disperse NPM1 from nucleoli and entrap rRNA in static condensates in a DPR-length-dependent manner. We propose that R-rich DPR toxicity involves disrupting the role of phase separation by NPM1 in organizing ribosomal proteins and RNAs within the nucleolus.

| S-EPMC6525025 | biostudies-literature

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent nuclear accumulation of Staufen in neurons.

Project description:RNA-binding proteins (RBPs) play essential roles in diverse cellular processes through post-transcriptional regulation of RNAs. The subcellular localization of RBPs is thus under tight control, the breakdown of which is associated with aberrant cytoplasmic accumulation of nuclear RBPs such as TDP-43 and FUS, well-known pathological markers for amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Here, we report in Drosophila model for ALS/FTD that nuclear accumulation of a cytoplasmic RBP Staufen may be a new pathological feature. We found that in Drosophila C4da neurons expressing PR36, one of the arginine-rich dipeptide repeat proteins (DPRs), Staufen accumulated in the nucleus in Importin- and RNA-dependent manner. Notably, expressing Staufen with exogenous NLS-but not with mutated endogenous NLS-potentiated PR-induced dendritic defect, suggesting that nuclear-accumulated Staufen can enhance PR toxicity. PR36 expression increased Fibrillarin staining in the nucleolus, which was enhanced by heterozygous mutation of stau (stau+/-), a gene that codes Staufen. Furthermore, knockdown of fib, which codes Fibrillarin, exacerbated retinal degeneration mediated by PR toxicity, suggesting that increased amount of Fibrillarin by stau+/- is protective. stau+/- also reduced the amount of PR-induced nuclear-accumulated Staufen and mitigated retinal degeneration and rescued viability of flies expressing PR36. Taken together, our data show that nuclear accumulation of Staufen in neurons may be an important pathological feature contributing to the pathogenesis of ALS/FTD.

| S-EPMC8188407 | biostudies-literature

Co-expression of C9orf72 related dipeptide-repeats over 1000 repeat units reveals age- and combination-specific phenotypic profiles in Drosophila.

Project description:A large intronic hexanucleotide repeat expansion (GGGGCC) within the C9orf72 (C9orf72-SMCR8 Complex Subunit) locus is the most prevalent genetic cause of both Frontotemporal Dementia (FTD) and Motor Neuron Disease (MND). In patients this expansion is typically hundreds to thousands of repeat units in length. Repeat associated non-AUG translation of the expansion leads to the formation of toxic, pathological Dipeptide-Repeat Proteins (DPRs). To date there remains a lack of in vivo models expressing C9orf72 related DPRs with a repeat length of more than a few hundred repeats. As such our understanding of how physiologically relevant repeat length DPRs effect the nervous system in an ageing in vivo system remains limited. In this study we generated Drosophila models expressing DPRs over 1000 repeat units in length, a known pathological length in humans. Using these models, we demonstrate each DPR exhibits a unique, age-dependent, phenotypic and pathological profile. Furthermore, we show co-expression of specific DPR combinations leads to distinct, age-dependent, phenotypes not observed through expression of single DPRs. We propose these models represent a unique, in vivo, tool for dissecting the molecular mechanisms implicated in disease pathology, opening up new avenues in the study of both MND and FTD.

| S-EPMC7487709 | biostudies-literature

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