title: Changes in intranuclear mobility of mature snRNPs provide a mechanism for splicing defects in spinal muscular atrophy.
abstract: It is becoming increasingly clear that defects in RNA metabolism can lead to disease. Spinal muscular atrophy (SMA), a leading genetic cause of infant mortality, results from insufficient amounts of survival motor neuron (SMN) protein. SMN is required for the biogenesis of small nuclear ribonucleoproteins (snRNPs): essential components of the spliceosome. Splicing abnormalities have been detected in models of SMA but it is unclear how lowered SMN affects the fidelity of pre-mRNA splicing. We have examined the dynamics of mature snRNPs in cells depleted of SMN and demonstrated that SMN depletion increases the mobility of mature snRNPs within the nucleus. To dissect the molecular mechanism by which SMN deficiency affects intranuclear snRNP mobility, we employed a panel of inhibitors of different stages of pre-mRNA processing. This in vivo modelling demonstrates that snRNP mobility is altered directly as a result of impaired snRNP maturation. Current models of nuclear dynamics predict that subnuclear structures, including the spliceosome, form by self-organization mediated by stochastic interactions between their molecular components. Thus, alteration of the intranuclear mobility of snRNPs provides a molecular mechanism for splicing defects in SMA.
authors.affiliation: University of St Andrews, School of Biology, St Andrews, Fife, UK.
authors.forename: Allyson Kara
authors.initials: AK
authors.lastname: Clelland
authors.forename: Alexandra Beatrice E
authors.initials: AB
authors.lastname: Bales
authors.forename: Judith Elizabeth
authors.initials: JE
authors.lastname: Sleeman
mesh_terms: D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology*; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference / Q000187:drug effects; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics*; D034741:RNA, Small Interfering / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism; D017411:Ribonucleoproteins, Small Nuclear / Q000378:metabolism*; D017381:Spliceosomes / Q000187:drug effects / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D034741:RNA, Small Interfering; D017412:Ribonucleoprotein, U1 Small Nuclear; D017411:Ribonucleoproteins, Small Nuclear; C526471:SMN1 protein, human; D055533:Survival of Motor Neuron 1 Protein; C552126:U11-U12 small nuclear ribonucleoprotein; C038753:leptomycin B