Pathological impact of SMN2 mis-splicing in adult SMA mice

Sahashi, K., Ling, K. K., Hua, Y., Wilkinson, J. E., Nomakuchi, T., Rigo, F., Hung, G., Xu, D., Jiang, Y. P., Lin, R. Z., Ko, C. P., Bennett, C. F., Krainer, A. R. (September 2013) Pathological impact of SMN2 mis-splicing in adult SMA mice. EMBO Molecular Medicine, 5 (10). pp. 1586-1601. ISSN 17574676 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24014320
DOI: 10.1002/emmm.201302567

Abstract

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.

Item Type: Paper
Subjects: diseases & disorders > congenital hereditary genetic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing
diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > splicing factor
CSHL Authors:
Communities: CSHL Cancer Center Program > Gene Regulation and Cell Proliferation
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
CSHL Cancer Center Shared Resources > Histology Service
CSHL Cancer Center Shared Resources > Microscopy Service
CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > Animal Tissue and Imaging Service
Depositing User: Matt Covey
Date: 9 September 2013
Date Deposited: 20 Sep 2013 14:17
Last Modified: 29 Oct 2015 20:43
PMCID: PMC3799581
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28571

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