Sequestration of DROSHA and DGCR8 by expanded CGG RNA Repeats Alters microRNA processing in fragile X-associated tremor/ataxia syndrome

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

Research output: Contribution to journalArticle

129 Citations (Scopus)

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. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the accumulation of mutant RNAs containing expanded CGG repeats. Charlet-Berguerand and colleagues now find that DROSHA-DGCR8, the enzymatic complex that processes microRNAs, is sequestered within nuclear aggregates of CGG RNA repeats. In addition, they show that the processing of microRNA is reduced in patients with FXTAS. These data suggest a model in which a human neurodegenerative disease is linked to sequestration of the microRNA-processing machinery.

Original languageEnglish (US)
Pages (from-to)869-880
Number of pages12
JournalCell Reports
Volume3
Issue number3
DOIs
StatePublished - 2013

Fingerprint

MicroRNAs
RNA
Neurodegenerative Diseases
Processing
Neurodegenerative diseases
RNA-Binding Proteins
Machinery
Nuclear RNA
5' Untranslated Regions
Cell death
Fragile X Tremor Ataxia Syndrome
Brain
Cell Death
Cells
Tissue

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Sequestration of DROSHA and DGCR8 by expanded CGG RNA Repeats Alters microRNA processing in fragile X-associated tremor/ataxia syndrome. / Sellier, Chantal; Freyermuth, Fernande; Tabet, Ricardos; Tran, Tuan; He, Fang; Ruffenach, Frank; Alunni, Violaine; Moine, Herve; Thibault, Christelle; Page, Adeline; Tassone, Flora; Willemsen, Rob; Disney, Matthew D.; Hagerman, Paul J; Todd, Peter K.; Charlet-Berguerand, Nicolas.

In: Cell Reports, Vol. 3, No. 3, 2013, p. 869-880.

Research output: Contribution to journalArticle

Sellier, C, Freyermuth, F, Tabet, R, Tran, T, He, F, Ruffenach, F, Alunni, V, Moine, H, Thibault, C, Page, A, Tassone, F, Willemsen, R, Disney, MD, Hagerman, PJ, Todd, PK & Charlet-Berguerand, N 2013, 'Sequestration of DROSHA and DGCR8 by expanded CGG RNA Repeats Alters microRNA processing in fragile X-associated tremor/ataxia syndrome', Cell Reports, vol. 3, no. 3, pp. 869-880. https://doi.org/10.1016/j.celrep.2013.02.004
Sellier, Chantal ; Freyermuth, Fernande ; Tabet, Ricardos ; Tran, Tuan ; He, Fang ; Ruffenach, Frank ; Alunni, Violaine ; Moine, Herve ; Thibault, Christelle ; Page, Adeline ; Tassone, Flora ; Willemsen, Rob ; Disney, Matthew D. ; Hagerman, Paul J ; Todd, Peter K. ; Charlet-Berguerand, Nicolas. / Sequestration of DROSHA and DGCR8 by expanded CGG RNA Repeats Alters microRNA processing in fragile X-associated tremor/ataxia syndrome. In: Cell Reports. 2013 ; Vol. 3, No. 3. pp. 869-880.
@article{539f83540ccf43d5a02956545c3dd5e7,
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. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the accumulation of mutant RNAs containing expanded CGG repeats. Charlet-Berguerand and colleagues now find that DROSHA-DGCR8, the enzymatic complex that processes microRNAs, is sequestered within nuclear aggregates of CGG RNA repeats. In addition, they show that the processing of microRNA is reduced in patients with FXTAS. These data suggest a model in which a human neurodegenerative disease is linked to sequestration of the microRNA-processing machinery.",
author = "Chantal Sellier and Fernande Freyermuth and Ricardos Tabet and Tuan Tran and Fang He and Frank Ruffenach and Violaine Alunni and Herve Moine and Christelle Thibault and Adeline Page and Flora Tassone and Rob Willemsen and Disney, {Matthew D.} and Hagerman, {Paul J} and Todd, {Peter K.} and Nicolas Charlet-Berguerand",
year = "2013",
doi = "10.1016/j.celrep.2013.02.004",
language = "English (US)",
volume = "3",
pages = "869--880",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Sequestration of DROSHA and DGCR8 by expanded CGG RNA Repeats Alters microRNA processing in fragile X-associated tremor/ataxia syndrome

AU - Sellier, Chantal

AU - Freyermuth, Fernande

AU - Tabet, Ricardos

AU - Tran, Tuan

AU - He, Fang

AU - Ruffenach, Frank

AU - Alunni, Violaine

AU - Moine, Herve

AU - Thibault, Christelle

AU - Page, Adeline

AU - Tassone, Flora

AU - Willemsen, Rob

AU - Disney, Matthew D.

AU - Hagerman, Paul J

AU - Todd, Peter K.

AU - Charlet-Berguerand, Nicolas

PY - 2013

Y1 - 2013

N2 - 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. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the accumulation of mutant RNAs containing expanded CGG repeats. Charlet-Berguerand and colleagues now find that DROSHA-DGCR8, the enzymatic complex that processes microRNAs, is sequestered within nuclear aggregates of CGG RNA repeats. In addition, they show that the processing of microRNA is reduced in patients with FXTAS. These data suggest a model in which a human neurodegenerative disease is linked to sequestration of the microRNA-processing machinery.

AB - 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. Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by the accumulation of mutant RNAs containing expanded CGG repeats. Charlet-Berguerand and colleagues now find that DROSHA-DGCR8, the enzymatic complex that processes microRNAs, is sequestered within nuclear aggregates of CGG RNA repeats. In addition, they show that the processing of microRNA is reduced in patients with FXTAS. These data suggest a model in which a human neurodegenerative disease is linked to sequestration of the microRNA-processing machinery.

UR - http://www.scopus.com/inward/record.url?scp=84875804170&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84875804170&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2013.02.004

DO - 10.1016/j.celrep.2013.02.004

M3 - Article

C2 - 23478018

AN - SCOPUS:84875804170

VL - 3

SP - 869

EP - 880

JO - Cell Reports

JF - Cell Reports

SN - 2211-1247

IS - 3

ER -