title: The loss of the snoRNP chaperone Nopp140 from Cajal bodies of patient fibroblasts correlates with the severity of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a common autosomal recessive neurodegenerative disease caused by reduced survival motor neuron (SMN) levels. The assembly machinery containing SMN is implicated in the biogenesis of the spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN is present in both the cytoplasm and nucleus, where it transiently accumulates in subnuclear domains named Cajal bodies (CBs) and functions in the maturation of snRNPs and small nucleolar (sno)RNPs. The impact of lowering SMN levels on the composition of CBs in SMA cells is still not completely understood. Here, we analyse the CB composition in immortalized and primary fibroblasts from SMA patients. We show that the U snRNA export factors PHAX and chromosome region maintenance 1 and the box C/D snoRNP core protein fibrillarin concentrate in CBs from SMA cells, whereas the box H/ACA core proteins GAR1 and NAP57/dyskerin show reduced CB localization. Remarkably, the functional deficiency in SMA cells is associated with decreased localization of the snoRNP chaperone Nopp140 in CBs that correlates with disease severity. Indeed, RNA interference knockdown experiments in control fibroblasts demonstrate that SMN is required for accumulation of Nopp140 in CBs. Conversely, overexpression of SMN in SMA cells restores the CB localization of Nopp140, whereas SMN mutants found in SMA patients are defective in promoting the association of Nopp140 with CBs. Taken together, we demonstrate that only a subset of CB functions (as indicated by the association of representative factors) are impaired in SMA cells and, importantly, we identify the decrease of Nopp140 localization in CBs as a phenotypic marker for SMA.
authors.affiliation: Laboratoire de Biologie Cellulaire des Membranes, Department of Cell Biology, Institut Jacques Monod (IJM), UMR 7592 CNRS/Universités Paris 6 et 7, Paris Cedex 05, France.
authors.forename: Benoît
authors.initials: B
authors.lastname: Renvoisé
authors.forename: Sabrina
authors.initials: S
authors.lastname: Colasse
authors.forename: Philippe
authors.initials: P
authors.lastname: Burlet
authors.forename: Louis
authors.initials: L
authors.lastname: Viollet
authors.forename: U Thomas
authors.initials: UT
authors.lastname: Meier
authors.forename: Suzie
authors.initials: S
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D020541:Coiled Bodies / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D018832:Molecular Chaperones / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology*; D050505:Mutant Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D020718:Ribonucleoproteins, Small Nucleolar / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism
chemical_list: D018832:Molecular Chaperones; D050505:Mutant Proteins; C075564:NOLC1 protein, human; D009687:Nuclear Proteins; D010750:Phosphoproteins; D020718:Ribonucleoproteins, Small Nucleolar; D055533:Survival of Motor Neuron 1 Protein