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: 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
• Journal: Cell reports (Cell Rep) Vol. 3 Issue 3 Pg. 869-80 (Mar 28 2013) ISSN: 2211-1247 [Electronic] United States
• PMID: 23478018 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• DGCR8 protein, human
• Dgcr8 protein, mouse
• MicroRNAs
• Proteins
• RNA-Binding Proteins
• DROSHA protein, human
• Drosha protein, mouse
• Ribonuclease III

Topics

• Animals
• Ataxia (genetics, metabolism)
• Brain (metabolism)
• Cell Death
• Fragile X Syndrome (genetics, metabolism)
• Humans
• Mice
• Mice, Inbred C57BL
• MicroRNAs (metabolism)
• Neurons (metabolism)
• Protein Binding
• Proteins (genetics, metabolism)
• RNA Processing, Post-Transcriptional
• RNA-Binding Proteins
• Ribonuclease III (genetics, metabolism)
• Transcription, Genetic
• Tremor (genetics, metabolism)
• Trinucleotide Repeat Expansion