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 language | English (US) |
|---|---|
| Pages (from-to) | 869-880 |
| Number of pages | 12 |
| Journal | Cell Reports |
| Volume | 3 |
| Issue number | 3 |
| DOIs | |
| State | Published - 2013 |
Fingerprint
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 journal › Article
}
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 -