title: Pathological impact of SMN2 mis-splicing in adult SMA mice.
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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Sahashi
authors.forename: Karen K Y
authors.initials: KK
authors.lastname: Ling
authors.forename: Yimin
authors.initials: Y
authors.lastname: Hua
authors.forename: John Erby
authors.initials: JE
authors.lastname: Wilkinson
authors.forename: Tomoki
authors.initials: T
authors.lastname: Nomakuchi
authors.forename: Frank
authors.initials: F
authors.lastname: Rigo
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.forename: David
authors.initials: D
authors.lastname: Xu
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Jiang
authors.forename: Richard Z
authors.initials: RZ
authors.lastname: Lin
authors.forename: Chien-Ping
authors.initials: CP
authors.lastname: Ko
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Adrian R
authors.initials: AR
authors.lastname: Krainer
mesh_terms: D000818:Animals; D001483:Base Sequence; D002490:Central Nervous System / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D012326:RNA Splicing / Q000187:drug effects; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D016376:Oligonucleotides, Antisense; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D007334:Insulin-Like Growth Factor I
keywords: SMN2; adult-onset SMA; pathology; spinal muscular atrophy; splicing