RESUMO
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a recently described neurodegenerative disorder of older adult carriers of premutation alleles (60-200 CGG repeats) in the fragile X mental retardation gene (FMR1). It has been proposed that FXTAS is an RNA-mediated neurodegenerative disease caused by the titration of RNA-binding proteins by the CGG repeats. To test this hypothesis, we utilize a transgenic Drosophila model of FXTAS that expresses a premutation-length repeat (90 CGG repeats) from the 5' UTR of the human FMR1 gene and displays neuronal degeneration. Here, we show that overexpression of RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppresses the phenotype of the CGG transgenic fly. Furthermore, we show that hnRNP A2/B1 directly interacts with riboCGG repeats and that the CUGBP1 protein interacts with the riboCGG repeats via hnRNP A2/B1.
Assuntos
Proteínas de Drosophila/metabolismo , Síndrome do Cromossomo X Frágil/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , Animais , Animais Geneticamente Modificados , Proteínas CELF1 , Modelos Animais de Doenças , Drosophila , Proteínas de Drosophila/genética , Olho/patologia , Olho/ultraestrutura , Proteína do X Frágil da Deficiência Intelectual/genética , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/patologia , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/genética , Imunoprecipitação/métodos , Microscopia Eletrônica de Varredura/métodos , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas de Ligação a RNA/genéticaRESUMO
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.