Pathological impact of SMN2 mis‐splicing in adult SMA mice. Issue 10 (9th September 2013)

• Record Type: Journal Article
• Authors: Sahashi, Kentaro; Ling, Karen K. Y.; Hua, Yimin; Wilkinson, John Erby; Nomakuchi, Tomoki; Rigo, Frank; Hung, Gene; Xu, David; Jiang, Ya‐Ping; Lin, Richard Z.; Ko, Chien‐Ping; Bennett, C. Frank; Krainer, Adrian R.
• Is Part Of: EMBO molecular medicine. Volume 5:Issue 10(2013:Oct.)
• Page Start: 1586
• Page End: 1601
• Publication Date: 2013-09-09
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201302567
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="emmm201302567-sec-0001" sec-type="section"> <p>Loss‐of‐function mutations in <italic>SMN1</italic> cause spinal muscular atrophy (SMA), a leading genetic cause of infant mortality. The related <italic>SMN2</italic> 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 <italic>SMN2</italic> mis‐splicing. Intracerebroventricular ASO injection in adult <italic>SMN2</italic>‐transgenic mice phenocopies key aspects of adult‐onset SMA, including delayed‐onset motor dysfunction and relevant histopathological features. <italic>SMN2</italic> mis‐splicing increases during late‐stage disease, likely accelerating disease progression. Systemic ASO injection in adult mice causes peripheral <italic>SMN2</italic> 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.</p> </sec> </abstract>