Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat

Abstract

Fragile X Syndrome is the most common form of hereditary mental retardation. It is caused by a large expansion of the CGG trinucleotide repeat (>200 repeats) in the 5'-untranslated region (UTR) of the FMR1 gene that leads to silencing of its transcript. Individuals with CGG repeat expansions approximately between 60 and 200 are referred to as premutation carriers. Fragile X-associated tremor and ataxia syndrome (FXTAS), an RNA-mediated neurodegenerative disease has been described in up to 50% of males carrying premutation alleles. FRAXE, the most common form of non-syndromic X-linked mental retardation, is caused by expansion of a CCG trinucleotide repeat (>200) in the 5'-UTR of the FMR2 gene. While the FRAXE premutation length repeat is observed in the general population, there has not yet been a report of a neurodegenerative phenotype associated with these alleles. In this study, we show that the CCG premutation length repeat leads to an RNA-mediated neurodegenerative phenotype in a Drosophila model. Furthermore, we show that co-expression of both the CCG and CGG-containing RNAs suppresses their independent toxicity and is dependent on the RNAi pathway. These data support the concept that RNA toxicity is the mechanism of neuronal toxicity and suggests potential reversal of RNA-mediated phenotypes with complementary RNA molecules.

The biological effects of simple tandem repeats: Lessons from the repeat expansion diseases: Table 1.

“…An RNA-mediated mechanism of pathology is supported by the observations that RNA with large numbers of CGG repeats is toxic to human cells (Arocena et al 2005;Handa et al 2005) and causes neurodegeneration in flies (Jin et al 2003). Some of the antisense transcripts seen in carriers of alleles with 55-200 repeats also contain the repeat region (Ladd et al 2007), and CCG repeats also cause neurodegeneration in flies (Sofola et al 2007a). The antisense transcript may thus also contribute to FXTAS pathology.…”

Repeat‐associated non‐AUG translation from antisense CCG repeats in fragile X tremor/ataxia syndrome

“…ASFMR1 mRNA is ubiquitously expressed in human tissue, with highest expression in the brain, and its expression is elevated in FXTAS patients and models 20 . Because the CCG repeat in the ASFMR1 transcript is predicted to form a stable secondary structure 22 , we hypothesized that it might support RAN translation and potentially contribute to disease pathogenesis in FXTAS, similar to the CGG repeat in the sense transcript 23 . Here we provide evidence from cellular models that the CCG repeat can support RAN translation in all three reading frames to produce homopolymeric proteins.…”

RNA toxicity and foci formation in microsatellite expansion diseases

“…Second, transcription efficiency of FMR1 is significantly elevated in FXTAS patients and mice, while the FMR protein (FMRP) level remains largely unchanged [113–115]. Third, co-expression of both CCG and CGG-containing RNA suppresses their independent toxicity [116]. Fourth, large ubiquitin-positive nuclear inclusions have been found in FXTAS tissues.…”