Discovering the 3' UTR-mediated regulation of alpha-synuclein

Marchese, Domenica, 1986-; Botta Orfila, Teresa; Cirillo, Davide; Rodríguez, Juan Antonio; Livi, Carmen Maria; Fernández-Santiago, Ruben; Ezquerra, Mario; Martí, Maria José; Bechara, Elias; Tartaglia, Gian Gaetano; Catalan multiple system atrophy-registry (CMSAR)

Discovering the 3' UTR-mediated regulation of alpha-synuclein

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dc.contributor.author Marchese, Domenica, 1986-ca
dc.contributor.author Botta Orfila, Teresaca
dc.contributor.author Cirillo, Davideca
dc.contributor.author Rodríguez, Juan Antonioca
dc.contributor.author Livi, Carmen Mariaca
dc.contributor.author Fernández-Santiago, Rubenca
dc.contributor.author Ezquerra, Marioca
dc.contributor.author Martí, Maria Joséca
dc.contributor.author Bechara, Eliasca
dc.contributor.author Tartaglia, Gian Gaetanoca
dc.contributor.author Catalan multiple system atrophy-registry (CMSAR)ca
dc.date.accessioned 2018-06-28T07:40:33Z
dc.date.available 2018-06-28T07:40:33Z
dc.date.issued 2017
dc.description.abstract Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.
dc.description.sponsorship Spanish Ministry of Economy and Competitiveness, 'Centro de Excelencia Severo Ochoa 2013-2017'; CERCA Programme / Generalitat de Catalunya; European Research Council [RIBOMYLOME_309545]; Spanish Ministry of Economy and Competitiveness [BFU2014-55054-P]; 'Fundació La Marató de TV3' [PI043296]. Funding for open access charge: European Research Council (RIBOMYLOME_309545) Fundació la Marató de TV3 [PI043296].
dc.format.mimetype application/pdf
dc.identifier.citation Marchese D, Botta-Orfila T, Cirillo D, Rodriguez JA, Livi CM, Fernández-Santiago R et al. Catalan MSA Registry (CMSAR). Discovering the 3' UTR-mediated regulation of alpha-synuclein. Nucleic Acids Res. 2017 Dec 15;45(22):12888-903. DOI: 10.1093/nar/gkx1048
dc.identifier.doi http://dx.doi.org/10.1093/nar/gkx1048
dc.identifier.issn 0305-1048
dc.identifier.uri http://hdl.handle.net/10230/34993
dc.language.iso eng
dc.publisher Oxford University Pressca
dc.relation.ispartof Nucleic Acids Research. 2017 Dec 15;45(22):12888-903
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/309545
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2014–55054-P
dc.rights © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.keyword Eval-like protein 1
dc.subject.keyword Gene expression regulation
dc.subject.keyword Parkinson disease
dc.subject.keyword Nucleus accumbens
dc.subject.keyword Rna-binding proteins
dc.title Discovering the 3' UTR-mediated regulation of alpha-synucleinca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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