Human Molecular Genetics Advance Access published online on July 17, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm186
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Argonaute-2 dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeat
1 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 2 Department of Human Genetics, Emory University School of Medicine, Atlanta GA 30322.
* Correspondence should be addressed to David Nelson, Baylor College of Medicine, One Baylor Plaza, Houston, TX. Phone: + 1 7137983122, Fax: + 1 7137981116, nelson{at}bcm.tmc.edu
Received May 10, 2007; Revised July 6, 2007; Accepted July 6, 2007
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 of the FMR1 gene that leads to silencing of its transcript. Individuals with CGG repeat expansions 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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