Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome
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, thu...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2013-03-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124713000636 |
| _version_ | 1828496446182129664 |
|---|---|
| author | Chantal Sellier Fernande Freyermuth Ricardos Tabet Tuan Tran Fang He Frank Ruffenach Violaine Alunni Herve Moine Christelle Thibault Adeline Page Flora Tassone Rob Willemsen Matthew D. Disney Paul J. Hagerman Peter K. Todd Nicolas Charlet-Berguerand |
| author_facet | Chantal Sellier Fernande Freyermuth Ricardos Tabet Tuan Tran Fang He Frank Ruffenach Violaine Alunni Herve Moine Christelle Thibault Adeline Page Flora Tassone Rob Willemsen Matthew D. Disney Paul J. Hagerman Peter K. Todd Nicolas Charlet-Berguerand |
| author_sort | Chantal Sellier |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T12:30:01Z |
| format | Article |
| id | doaj.art-1c7e384c7f084d4bbbe622f19b4549da |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-11T12:30:01Z |
| publishDate | 2013-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1c7e384c7f084d4bbbe622f19b4549da2022-12-22T01:07:16ZengElsevierCell Reports2211-12472013-03-013386988010.1016/j.celrep.2013.02.004Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia SyndromeChantal Sellier0Fernande Freyermuth1Ricardos Tabet2Tuan Tran3Fang He4Frank Ruffenach5Violaine Alunni6Herve Moine7Christelle Thibault8Adeline Page9Flora Tassone10Rob Willemsen11Matthew D. Disney12Paul J. Hagerman13Peter K. Todd14Nicolas Charlet-Berguerand15Department of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceDepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceM.I.N.D. Institute, University of California, Davis, Sacramento, CA 95817, USADepartment of Clinical Genetics, Erasmus MC, Rotterdam 3000 DR, The NetherlandsDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USAM.I.N.D. Institute, University of California, Davis, Sacramento, CA 95817, USADepartment of Neurology, University of Michigan, Ann Arbor, MI 48109, USADepartment of Translational Medicine, IGBMC, Illkirch 67400, FranceFragile 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.http://www.sciencedirect.com/science/article/pii/S2211124713000636 |
| spellingShingle | Chantal Sellier Fernande Freyermuth Ricardos Tabet Tuan Tran Fang He Frank Ruffenach Violaine Alunni Herve Moine Christelle Thibault Adeline Page Flora Tassone Rob Willemsen Matthew D. Disney Paul J. Hagerman Peter K. Todd Nicolas Charlet-Berguerand Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome Cell Reports |
| title | Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome |
| title_full | Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome |
| title_fullStr | Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome |
| title_full_unstemmed | Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome |
| title_short | Sequestration of DROSHA and DGCR8 by Expanded CGG RNA Repeats Alters MicroRNA Processing in Fragile X-Associated Tremor/Ataxia Syndrome |
| title_sort | sequestration of drosha and dgcr8 by expanded cgg rna repeats alters microrna processing in fragile x associated tremor ataxia syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2211124713000636 |
| work_keys_str_mv | AT chantalsellier sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT fernandefreyermuth sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT ricardostabet sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT tuantran sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT fanghe sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT frankruffenach sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT violainealunni sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT hervemoine sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT christellethibault sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT adelinepage sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT floratassone sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT robwillemsen sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT matthewddisney sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT pauljhagerman sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT peterktodd sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome AT nicolascharletberguerand sequestrationofdroshaanddgcr8byexpandedcggrnarepeatsaltersmicrornaprocessinginfragilexassociatedtremorataxiasyndrome |