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Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

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Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

dc.contributor.author	García López, Amparo
dc.contributor.author	Tessaro, Francesca
dc.contributor.author	Jonker, Hendrik R.A.
dc.contributor.author	Wacker, Anna
dc.contributor.author	Richter, Christian
dc.contributor.author	Comte, Arnaud
dc.contributor.author	Berntenis, Nikolaos
dc.contributor.author	Schmucki, Roland
dc.contributor.author	Hatje, Klas
dc.contributor.author	Petermann, Olivier
dc.contributor.author	Chiriano, Gianpaolo
dc.contributor.author	Perozzo, Remo
dc.contributor.author	Sciarra, Daniel
dc.contributor.author	Konieczny, Piotr
dc.contributor.author	Faustino, Ignacio
dc.contributor.author	Fournet, Guy
dc.contributor.author	Orozco, Modesto
dc.contributor.author	Artero Allepuz, Rubén D.
dc.contributor.author	Metzger, Friedrich
dc.contributor.author	Ebeling, Martin
dc.contributor.author	Goekjian, Peter
dc.contributor.author	Benoît, Joseph
dc.contributor.author	Schwalbe, Harald
dc.contributor.author	Scapozza, Leonardo
dc.date.accessioned	2022-03-31T13:29:23Z
dc.date.available	2022-03-31T13:29:23Z
dc.date.issued	2018
dc.identifier.citation	García López, Amparo Tessaro, Francesca Jonker, Hendrik R.A. Wacker, Anna Richter, Christian Comte, Arnaud Berntenis, Nikolaos Schmucki, Roland Hatje, Klas Petermann, Olivier Chiriano, Gianpaolo Perozzo, Remo Sciarra, Daniel Konieczny, Piotr Faustino, Ignacio Fournet, Guy Orozco, Modesto Artero Allepuz, Rubén D. Metzger, Friedrich Ebeling, Martin Goekjian, Peter Benoît, Joseph Schwalbe, Harald Scapozza, Leonardo 2018 Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes Nature Communications 9 2032
dc.identifier.uri	https://hdl.handle.net/10550/82112
dc.description.abstract	Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted.
dc.language.iso	eng
dc.relation.ispartof	Nature Communications, 2018, vol. 9, num. 2032
dc.subject	RNA
dc.subject	Genètica molecular
dc.subject	Biotecnologia
dc.title	Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
dc.type	journal article	es_ES
dc.date.updated	2022-03-31T13:29:23Z
dc.identifier.doi	10.1038/s41467-018-04110-1
dc.identifier.idgrec	123880
dc.rights.accessRights	open access	es_ES