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Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat
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posted on 2023-06-09, 08:33 authored by Oyinkan Adesakin, Peng Jin, Juan Botas, David NelsonFragile 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.
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- Published
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- Published version
Journal
Human Molecular GeneticsISSN
0964-6906Publisher
Oxford University PressExternal DOI
Issue
19Volume
16Page range
2326-2332Department affiliated with
- Neuroscience Publications
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- No
Peer reviewed?
- Yes
Legacy Posted Date
2017-11-02First Compliant Deposit (FCD) Date
2017-11-02Usage metrics
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