Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome
| Autor: | Violaine Alunni, Fernande Freyermuth, Hervé Moine, Rob Willemsen, Chantal Sellier, Flora Tassone, Fang He, Peter K. Todd, Tuan Tran, Paul J. Hagerman, Ricardos Tabet, Matthew D. Disney, Frank Ruffenach, Nicolas Charlet-Berguerand, Christelle Thibault, Adeline Page |
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| Přispěvatelé: | Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Collège de France (CdF (institution)), Scripps Research Institute, University of Michigan [Ann Arbor], University of Michigan System, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Surgery, Clinical Genetics |
| Jazyk: | angličtina |
| Rok vydání: | 2013 |
| Předmět: |
Ribonuclease III
congenital hereditary and neonatal diseases and abnormalities Transcription Genetic DGCR8 [SDV]Life Sciences [q-bio] Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Tremor microRNA medicine Animals Humans RNA Processing Post-Transcriptional lcsh:QH301-705.5 Drosha ComputingMilieux_MISCELLANEOUS 030304 developmental biology Neurons 0303 health sciences Cell Death biology Brain Proteins RNA-Binding Proteins RNA medicine.disease FMR1 Molecular biology nervous system diseases Mice Inbred C57BL Fragile X syndrome MicroRNAs lcsh:Biology (General) Fragile X Syndrome biology.protein Ataxia Trinucleotide Repeat Expansion Trinucleotide repeat expansion 030217 neurology & neurosurgery Protein Binding Fragile X-associated tremor/ataxia syndrome |
| Zdroj: | Cell Reports, Vol 3, Iss 3, Pp 869-880 (2013) Cell Reports Cell Reports, Elsevier Inc, 2013, 3 (3), pp.869-880. ⟨10.1016/j.celrep.2013.02.004⟩ Cell Reports, 3(3), 869-880. Cell Press |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2013.02.004⟩ |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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