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

GSE286170 Mus musculus Expression profiling by high throughput sequencing 4 samples Submitted 2025/12/15 Platform GPL24247
Summary
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.
Published in
Integrative transcriptome-wide association analyses reveal PRKCG-linked GABAergic dysfunction in Fragile X-associated tremor/ataxia syndrome
Jin Y, Cao Y, Ma W et al. · Nature communications 2026 · PMID 41507195 · doi:10.1038/s41467-025-68163-9
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Also filed as BioProject PRJNA1208043 and SRA study SRP556075. Searching any of these in the dataset finder brings you back here.

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