Pathological impact of SMN 2 mis‐splicing in adult SMA mice
| Autor: | C. Frank Bennett, Tomoki T. Nomakuchi, Karen K. Y. Ling, Richard Z. Lin, Yimin Hua, Gene Hung, Ya Ping Jiang, Chien-Ping Ko, Kentaro Sahashi, Frank Rigo, John E. Wilkinson, Adrian R. Krainer, David Xu |
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| Rok vydání: | 2013 |
| Předmět: |
Central Nervous System
Pathology medicine.medical_specialty Time Factors RNA Splicing Central nervous system Mice Transgenic SMN1 Biology Muscular Atrophy Spinal Pathogenesis Mice splicing Splicing factor adult-onset SMA medicine Animals Humans Insulin-Like Growth Factor I Pathological Research Articles spinal muscular atrophy Phenocopy Base Sequence Myocardium Spinal muscular atrophy Oligonucleotides Antisense SMA medicine.disease Survival of Motor Neuron 1 Protein nervous system diseases Survival of Motor Neuron 2 Protein medicine.anatomical_structure Liver Molecular Medicine pathology SMN2 |
| Zdroj: | EMBO Molecular Medicine |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | Loss-of-function mutations in SMN1 cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related SMN2 gene expresses suboptimal levels of functional SMN protein, due to a splicing defect. Many SMA patients reach adulthood, and there is also adult-onset (type IV) SMA. There is currently no animal model for adult-onset SMA, and the tissue-specific pathogenesis of post-developmental SMN deficiency remains elusive. Here, we use an antisense oligonucleotide (ASO) to exacerbate SMN2 mis-splicing. Intracerebroventricular ASO injection in adult SMN2-transgenic mice phenocopies key aspects of adult-onset SMA, including delayed-onset motor dysfunction and relevant histopathological features. SMN2 mis-splicing increases during late-stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral SMN2 mis-splicing and affects prognosis, eliciting marked liver and heart pathologies, with decreased IGF1 levels. ASO dose–response and time-course studies suggest that only moderate SMN levels are required in the adult central nervous system, and treatment with a splicing-correcting ASO shows a broad therapeutic time window. We describe distinctive pathological features of adult-onset and early-onset SMA. |
| Databáze: | OpenAIRE |
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