title: MicroRNA-277 modulates the neurodegeneration caused by Fragile X premutation rCGG repeats.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder, has been recognized in older male fragile X premutation carriers and is uncoupled from fragile X syndrome. Using a Drosophila model of FXTAS, we previously showed that transcribed premutation repeats alone are sufficient to cause neurodegeneration. MiRNAs are sequence-specific regulators of post-transcriptional gene expression. To determine the role of miRNAs in rCGG repeat-mediated neurodegeneration, we profiled miRNA expression and identified selective miRNAs, including miR-277, that are altered specifically in Drosophila brains expressing rCGG repeats. We tested their genetic interactions with rCGG repeats and found that miR-277 can modulate rCGG repeat-mediated neurodegeneration. Furthermore, we identified Drep-2 and Vimar as functional targets of miR-277 that could modulate rCGG repeat-mediated neurodegeneration. Finally, we found that hnRNP A2/B1, an rCGG repeat-binding protein, can directly regulate the expression of miR-277. These results suggest that sequestration of specific rCGG repeat-binding proteins could lead to aberrant expression of selective miRNAs, which may modulate the pathogenesis of FXTAS by post-transcriptionally regulating the expression of specific mRNAs involved in FXTAS.
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Huiping
authors.initials: H
authors.lastname: Tan
authors.forename: Mickael
authors.initials: M
authors.lastname: Poidevin
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.forename: Dahua
authors.initials: D
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
mesh_terms: D000818:Animals; D051186:Armadillo Domain Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D020869:Gene Expression Profiling; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D051186:Armadillo Domain Proteins; C402282:Drep2 protein, Drosophila; D029721:Drosophila Proteins; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; D035683:MicroRNAs; C113448:vimar protein, Drosophila