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Autor(en) / Beteiligte

Titel

SMN2 splice modulators enhance U1-pre-mRNA association and rescue SMA mice

Ist Teil von

Ort / Verlag

United States

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

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.

Sprache: Englisch
Identifikatoren: eISSN: 1552-4469
DOI: 10.1038/nchembio.1837
Titel-ID: cdi_pubmed_primary_26030728

Format: –
Schlagworte: Alternative Splicing, Animals, Binding Sites, Disease Models, Animal, Female, Gene Expression, Humans, Mice, Mice, Transgenic, Models, Molecular, Muscular Atrophy, Spinal - drug therapy, Muscular Atrophy, Spinal - metabolism, Muscular Atrophy, Spinal - mortality, Muscular Atrophy, Spinal - pathology, Protein Binding - drug effects, Protein Stability - drug effects, Proteolysis, Ribonucleoprotein, U1 Small Nuclear - agonists, Ribonucleoprotein, U1 Small Nuclear - chemistry, Ribonucleoprotein, U1 Small Nuclear - metabolism, RNA Precursors - agonists, RNA Precursors - chemistry, RNA Precursors - metabolism, RNA, Double-Stranded - agonists, RNA, Double-Stranded - chemistry, RNA, Double-Stranded - metabolism, Small Molecule Libraries - chemical synthesis, Small Molecule Libraries - metabolism, Small Molecule Libraries - pharmacology, Survival Analysis, Survival of Motor Neuron 2 Protein - chemistry, Survival of Motor Neuron 2 Protein - genetics, Survival of Motor Neuron 2 Protein - metabolism

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