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A critical role of GABAergic neurons in driving CGG repeat toxicity associated with Fragile X Premutation Carriers [scRNA-Seq]

ABSTRACT: Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion (55-200) in the 5′ UTR of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. The molecular mechanisms of FXTAS involve the toxic effects of the expanded CGG repeat RNA and the repeat-associated non-AUG (RAN) translation product, the FMRpolyG peptide. To gain deeper insights into the pathogenesis of FXTAS, we performed comprehensive transcriptomic profiling of the brain of an FXTAS mouse model at both bulk and single-cell levels, which revealed pronounced dysregulation in inhibitory neurons of FXTAS animals. Further, conditional FXTAS mouse models demonstrated that the expression of expanded CGG repeats in GABAergic neurons alone was sufficient to induce key features associated with the expression of FMR1 premutation CGG repeats. Many of the dysregulated mRNAs in GABAergic neurons were found to be bound by hnRNPA2/B1, an RNA-binding protein sequestered by CGG repeat RNA.

ORGANISM(S): Mus musculus

PROVIDER: GSE286170 | GEO | 2025/12/15

REPOSITORIES: GEO

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A critical role of GABAergic neurons in driving CGG repeat toxicity associated with Fragile X Premutation Carriers

Project description:Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by a CGG repeat expansion (55-200) in the 5′ UTR of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. The molecular mechanisms of FXTAS involve the toxic effects of the expanded CGG repeat RNA and the repeat-associated non-AUG (RAN) translation product, the FMRpolyG peptide. To gain deeper insights into the pathogenesis of FXTAS, we performed comprehensive transcriptomic profiling of the brain of an FXTAS mouse model at both bulk and single-cell levels, which revealed pronounced dysregulation in inhibitory neurons of FXTAS animals. Further, conditional FXTAS mouse models demonstrated that the expression of expanded CGG repeats in GABAergic neurons alone was sufficient to induce key features associated with the expression of FMR1 premutation CGG repeats. Many of the dysregulated mRNAs in GABAergic neurons were found to be bound by hnRNPA2/B1, an RNA-binding protein sequestered by CGG repeat RNA.

2025-12-15 | GSE285979 | GEO

Proteins binding in vitro to normal and mutant FMR1 5'UTR mRNA

Project description:Expanded CGG repeats in the 5’UTR of fragile X messenger ribonucleoprotein 1 (FMR1) gene are translated to mutant protein containing polyglycine stretches (FMRpolyG), which evoke development of neurodegenerative disorder the fragile X-associated tremor/ataxia syndrome (FXTAS). However, little is known about the regulation of noncanonical translation of mutant FMR1 mRNA. Here, we show that insulin growth factor 2 binding proteins (IGF2BPs) directly bind to 5’UTR of FMR1 mRNA to selectively enhance biosynthesis of FMRpolyG.

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Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [FXTAS]

Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 5 control samples plus one biological replicate and 9 patients with CGG expansions in the 5'UTR of the FMR1 gene (being premutation carriers)

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Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [SHSY5Y]

Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5M-bM-^@M-^Y-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5M-bM-^@M-^Y-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF. In the study presented here, we have 6 biological replicats for the Mock conditions, 6 biological replicates for the expression of the wild type FMR1 5'UTR, 6 biological replicates for the expression of the mutant FMR1 5'UTR and 6 biological replicates for the overexpression of the muatnt FMR1 5'UTR.

2014-02-20 | E-GEOD-48902 | biostudies-arrayexpress

miRNA profiling of plasma from FMR1 premutation carriers

Project description:Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, life span. In particular, the expansions of the CGG-repeats stretch at the 5'-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. We profiled the miRNAs content of plasma from premutation carriers and controls. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers

2021-08-31 | GSE181018 | GEO

CGG repeat RNA binding protein capture identifies SRSF protein kinase 1 as a modulator of RAN translation and suppressor of repeat toxicity

Project description:Transcribed CGG repeat expansions cause the neurodegenerative disorder Fragile X-associated tremor/ataxia syndrome (FXTAS). CGG repeat RNAs sequester RNA-binding proteins (RBPs) into nuclear foci and undergo repeat-associated non-AUG (RAN) translation into toxic peptides in the cytoplasm. To identify proteins involved in these processes, we employed a CGG repeat RNA-tagging system to capture repeat associated RBPs by mass spectrometry in mammalian cells. We identified several SR (serine/arginine-rich domain) proteins that interact selectively with CGG repeats basally and under cellular stress. These same proteins modify toxicity in a Drosophila model of FXTAS. Genetic or pharmacological targeting of serine/arginine protein kinases (SRPKs) inhibits RAN translation in cells and toxicity in both FXTAS and C9orf72 ALS/FTD model flies. Furthermore, SRPK inhibitors suppressed CGG repeat toxicity in rodent neurons. These findings demonstrate roles for CGG repeat RNA binding proteins in repeat toxicity and support further evaluation of SRPK inhibitors in modulating RAN translation associated with repeat expansion disorders.

2021-09-28 | PXD027000 | Pride

Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [SHSY5Y]

Project description:Fragile X premutation carriers (fXPC) of the CGG expansion in the 5’-UTR of the fragile X mental retardation 1 (FMR1) gene are at high risk of Fragile X Tremor/Ataxia Syndrome (FXTAS), and females might undergo Premature Ovarian Failure (POF1). We have evaluated the peripheral blood gene expression profiles of fXPC and detected a strong deregulation of genes enriched in FXTAS-relevant biological pathways, including inflammation, and neuronal homeostasis and survival. More than 30% of differentially expressed correspond to long non-coding RNAs (lncRNAs). Several deregulated genes (CASP3, DFFA, APP, AKT1, COX6C, COX7B, SOD1, RNF10, HDAC5, ATXN7, ATXN3 and EAP1) were validated in brain samples of a mouse model of FXTAS and in neuronal cells expressing the expanded FMR1 5’-UTR. One of the validated genes is the early at menopause 1 (EAP1) gene. We confirmed the EAP1 deregulation both in male and female fXPC. Down-regulation was stronger in female fXPC with POF1 compared with female fXPC without POF1. Increased levels of FMR1 mRNA were detected in all brain areas of the CGG-KI mouse model. EAP1 was significantly downregulated in the brainstem and cerebellum of the KI mouse, suggesting that EAP1 levels in certain brain areas could contribute to POF in this model. All together, these results suggest that gene expression profiling in blood of fXPC reflects changes in the brain transcriptome that may underlie neuropathological aspects in FXTAS and of POF.

2014-02-20 | GSE48902 | GEO

Blood expression profiles of fragile X premutation carriers identify genes involved in neurodegenerative and infertility phenotypes [FXTAS]

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Mass-spectrometry based screening revealing proteins bound to FMR1 mRNA

Project description:Short nucleotide repeats are robustly distributed in human genome and contribute to pathogenesis of multiple neurodegenerative disorders such as Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). Pathogenesis of FXTAS is driven by premutation status of CGG repeats expansion (CGGexp) in the 5’UTR region of fragile X messenger ribonucleoprotein 1 (FMR1) gene, when CGG triplet varies between 55-200. One of the proposed molecular mechanism involved in disease progression is repeats associated non-AUG (RAN) translation, which results in the production of toxic aggregation-prone protein called FMRpolyG. Mechanistic insights of RAN translation remain elusive, therefore we aimed to identify novel RAN translation modifiers. In order to identify factors involved in FMRpolyG synthesis we applied RNA-tagging system combined with mass spectrometry (MS) based protein identification to elucidate pool of proteins natively bound to FMR1 transcript harboring CGGexp mimicking FXTAS premutation status. As a control RNAm we used construct enriched with G and C nucleotides (named GCrich RNA) to mimic GC content in investigated FMR1 mRNA. Overall, performed MS-based screening revealed novel proteins which bind specifically to 5’UTR of FMR1 with CGGexp in cellulo.

2025-05-26 | PXD047400 | Pride

Reversion of FMR1 methylation and silencing by editing the triplet repeats in Fragile-X iPSC-derived neurons

Project description:Fragile X syndrome (FXS) is the most common form of inherited intellectual disability, resulting from a CGG repeat expansion in the fragile X mental retardation 1 (FMR1) gene. Here we report a strategy for CGG repeat correction using CRISPR/Cas9 for targeted deletion in both embryonic stem cells and induced pluripotent stem cells derived from FXS patients. Following gene correction in FXS induced pluripotent stem cells, FMR1 expression was restored and sustained in neural precursor cells and mature neurons. Strikingly, after removal of the CGG repeats, the upstream CpG island of the FMR1 promoter showed extensive demethylation, an open chromatin state, and transcription initiation. These results suggest a silencing maintenance mechanism for the FMR1 promoter that is dependent on the existence of the CGG repeat expansion. Our strategy for deletion of trinucleotide repeats provides further insights into the molecular mechanisms of FXS and future therapies of trinucleotide repeat disorders.

2015-08-18 | GSE72114 | GEO

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