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

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

SRSF protein kinase 1 modulates RAN translation and suppresses CGG repeat toxicity

Project description: Not available

| S-SCDT-EMM-2021-14163 | biostudies-other

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

2025-12-15 | GSE286170 | GEO

Targeting the r(CGG) repeats that cause FXTAS with modularly assembled small molecules and oligonucleotides.

Project description: Not available

| S-EPMC4287843 | biostudies-literature