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

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.