SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice.
Nat Chem Biol
; 11(7): 511-7, 2015 Jul.
Article
en En
| MEDLINE
| ID: mdl-26030728
ABSTRACT
Spinal muscular atrophy (SMA), which results from the loss of expression of the survival of motor neuron-1 (SMN1) gene, represents the most common genetic cause of pediatric mortality. A duplicate copy (SMN2) is inefficiently spliced, producing a truncated and unstable protein. We describe herein a potent, orally active, small-molecule enhancer of SMN2 splicing that elevates full-length SMN protein and extends survival in a severe SMA mouse model. We demonstrate that the molecular mechanism of action is via stabilization of the transient double-strand RNA structure formed by the SMN2 pre-mRNA and U1 small nuclear ribonucleic protein (snRNP) complex. The binding affinity of U1 snRNP to the 5' splice site is increased in a sequence-selective manner, discrete from constitutive recognition. This new mechanism demonstrates the feasibility of small molecule-mediated, sequence-selective splice modulation and the potential for leveraging this strategy in other splicing diseases.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
ARN Bicatenario
/
Atrofia Muscular Espinal
/
Ribonucleoproteína Nuclear Pequeña U1
/
Empalme Alternativo
/
Bibliotecas de Moléculas Pequeñas
/
Proteína 2 para la Supervivencia de la Neurona Motora
Tipo de estudio:
Risk_factors_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
Asunto de la revista:
BIOLOGIA
/
QUIMICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Estados Unidos