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dc.contributor.authorTapia, Olga
dc.contributor.authorNarcís, Oriol J.
dc.contributor.authorRiancho, Javier
dc.contributor.authorTarabal Mostazo, Olga
dc.contributor.authorPiedrafita Llorens, Lídia
dc.contributor.authorCalderó i Pardo, Jordi
dc.contributor.authorBerciano, Maria T.
dc.contributor.authorLafarga, Miguel
dc.date.accessioned2020-01-14T13:01:54Z
dc.date.available2020-01-14T13:01:54Z
dc.date.issued2017
dc.identifier.issn0969-9961
dc.identifier.urihttp://hdl.handle.net/10459.1/67809
dc.description.abstractSpinal muscular atrophy (SMA) is caused by a homozygous deletion or mutation in the survival motor neuron 1 (SMN1) gene that leads to reduced levels of SMN protein resulting in degeneration of motor neurons (MNs). The best known functions of SMN is the biogenesis of spliceosomal snRNPs. Linked to this function, Cajal bodies (CBs) are involved in the assembly of spliceosomal (snRNPs) and nucleolar (snoRNPs) ribonucleoproteins required for pre-mRNA and pre-rRNA processing. Recent studies support that the interaction between CBs and nucleoli, which are especially prominent in neurons, is essential for the nucleolar rRNA homeostasis. We use the SMN∆7 murine model of type I SMA to investigate the cellular basis of the dysfunction of RNA metabolism in MNs. SMN deficiency in postnatal MNs produces a depletion of functional CBs and relocalization of coilin, which is a scaffold protein of CBs, in snRNP-free perinucleolar caps or within the nucleolus. Disruption of CBs is the earliest nuclear sign of MN degeneration. We demonstrate that depletion of CBs, with loss of CB-nucleolus interactions, induces a progressive nucleolar dysfunction in ribosome biogenesis. It includes reorganization and loss of nucleolar transcription units, segregation of dense fibrillar and granular components, retention of SUMO-conjugated proteins in intranucleolar bodies and a reactive, compensatory, up-regulation of mature 18S rRNA and genes encoding key nucleolar proteins, such as upstream binding factor, fibrillarin, nucleolin and nucleophosmin. We propose that CB depletion and nucleolar alterations are essential components of the dysfunction of RNA metabolism in SMA.ca_ES
dc.description.sponsorshipThis work was supported by the following grants: “Dirección General de Investigación” of Spain (BFU2014-54754-P), “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED; CB06/05/0037)” from Spain, and “Ministerio de Economía y Competitividad” of Spain cofinanced by FEDER (SAF2015-70801-R). Dr. Tapia is a recipient of a grant from SMA Europe cofinanced by FundAME (Spain) and "Instituto de Investigación Valdecilla" (IDIVAL; Next-Val) from Santander, Spain.ca_ES
dc.language.isoengca_ES
dc.publisherElsevierca_ES
dc.relationMINECO/PN2013-2016/BFU2014-54754-Pca_ES
dc.relationMINECO/PN2013-2016/SAF2015-70801-Rca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1016/j.nbd.2017.08.004ca_ES
dc.relation.ispartofNeurobiology of Disease, 2017, vol. 108, p. 83-99ca_ES
dc.rights(c) Elsevier, 2017ca_ES
dc.subjectSpinal muscular atrophyca_ES
dc.subjectMotor neuronsca_ES
dc.subjectCajal bodiesca_ES
dc.subjectNucleolar dysfunctionca_ES
dc.subjectProtein synthesis machineryca_ES
dc.titleCellular bases of the RNA metabolism dysfunction in motor neurons of a murine model of spinal muscular atrophy: Role of Cajal bodies and the nucleolusca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.identifier.idgrec025906
dc.type.versioninfo:eu-repo/semantics/submittedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1016/j.nbd.2017.08.004


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