title: Sequestration of DROSHA and DGCR8 by expanded CGG RNA repeats alters microRNA processing in fragile X-associated tremor/ataxia syndrome.
abstract: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the expansion of 55-200 CGG repeats in the 5' UTR of FMR1. These expanded CGG repeats are transcribed and accumulate in nuclear RNA aggregates that sequester one or more RNA-binding proteins, thus impairing their functions. Here, we have identified that the double-stranded RNA-binding protein DGCR8 binds to expanded CGG repeats, resulting in the partial sequestration of DGCR8 and its partner, DROSHA, within CGG RNA aggregates. Consequently, the processing of microRNAs (miRNAs) is reduced, resulting in decreased levels of mature miRNAs in neuronal cells expressing expanded CGG repeats and in brain tissue from patients with FXTAS. Finally, overexpression of DGCR8 rescues the neuronal cell death induced by expression of expanded CGG repeats. These results support a model in which a human neurodegenerative disease originates from the alteration, in trans, of the miRNA-processing machinery.
authors.affiliation: Department of Translational Medicine, IGBMC, Illkirch 67400, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.forename: Fernande
authors.initials: F
authors.lastname: Freyermuth
authors.forename: Ricardos
authors.initials: R
authors.lastname: Tabet
authors.forename: Tuan
authors.initials: T
authors.lastname: Tran
authors.forename: Fang
authors.initials: F
authors.lastname: He
authors.forename: Frank
authors.initials: F
authors.lastname: Ruffenach
authors.forename: Violaine
authors.initials: V
authors.lastname: Alunni
authors.forename: Herve
authors.initials: H
authors.lastname: Moine
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.forename: Adeline
authors.initials: A
authors.lastname: Page
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.forename: Rob
authors.initials: R
authors.lastname: Willemsen
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Disney
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hagerman
authors.forename: Peter K
authors.initials: PK
authors.lastname: Todd
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D016923:Cell Death; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D016601:RNA-Binding Proteins; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014202:Tremor / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: C474043:DGCR8 protein, human; C474044:Dgcr8 protein, mouse; D035683:MicroRNAs; D011506:Proteins; D016601:RNA-Binding Proteins; C517918:DROSHA protein, human; C513400:Drosha protein, mouse; D043244:Ribonuclease III