title: Reduced U snRNP assembly causes motor axon degeneration in an animal model for spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a motoneuron disease caused by reduced levels of survival motoneuron (SMN) protein. Previous studies have assigned SMN to uridine-rich small nuclear ribonucleoprotein particle (U snRNP) assembly, splicing, transcription, and RNA localization. Here, we have used gene silencing to assess the effect of SMN protein deficiency on U snRNP metabolism in living cells and organisms. In HeLa cells, we show that reduction of SMN to levels found in SMA patients impairs U snRNP assembly. In line with this, induced silencing of SMN expression in Xenopus laevis or zebrafish arrested embryonic development. Under less severe knock-down conditions, zebrafish embryos proceeded through development yet exhibited dramatic SMA-like motor axon degeneration. The same was observed after silencing two other essential factors in the U snRNP assembly pathway, Gemin2 and pICln. Importantly, the injection of purified U snRNPs into either SMN- or Gemin2-deficient embryos of Xenopus and zebrafish prevented developmental arrest and motoneuron degeneration, respectively. These findings suggest that motoneuron degeneration in SMA patients is a direct consequence of impaired production of U snRNPs.
authors.affiliation: Institute of Biochemistry and Institute of Physiological Chemistry, Biocenter of the University of Würzburg, D-97074 Würzburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Winkler
authors.forename: Christian
authors.initials: C
authors.lastname: Eggert
authors.forename: Dietmar
authors.initials: D
authors.lastname: Gradl
authors.forename: Gunter
authors.initials: G
authors.lastname: Meister
authors.forename: Marieke
authors.initials: M
authors.lastname: Giegerich
authors.forename: Doris
authors.initials: D
authors.lastname: Wedlich
authors.forename: Bernhard
authors.initials: B
authors.lastname: Laggerbauer
authors.forename: Utz
authors.initials: U
authors.lastname: Fischer
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000196:embryology / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics
chemical_list: C108381:GEMIN2 protein, human; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear