| First Author | Sahashi K | Year | 2013 |
| Journal | EMBO Mol Med | Volume | 5 |
| Issue | 10 | Pages | 1586-601 |
| PubMed ID | 24014320 | Mgi Jnum | J:234758 |
| Mgi Id | MGI:5790780 | Doi | 10.1002/emmm.201302567 |
| Citation | Sahashi K, et al. (2013) Pathological impact of SMN2 mis-splicing in adult SMA mice. EMBO Mol Med 5(10):1586-601 |
| abstractText | 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. |
