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http://hdl.handle.net/2445/120734
Title: | Discovering the 3′ UTR-mediated regulation of alpha-synuclein |
Author: | Marchese, Domenica Botta Orfila, Teresa Cirillo, Davide Rodriguez, Juan Antonio Livi, Carmen M. Fernández Santiago, Rubén Ezquerra, Mario Martí Domènech, Ma. Josep Bechara, Elias Tartaglia, Gian Gaetano Catalan MSA Registry (CMSAR) Ávila, Asunción Bayés Rusiñol, Àngels Caballol, Núria Calopa, Matilde Campdelacreu i Fumadó, Jaume Compta, Yaroslau Fàbregues, Oriol de Girado, Darly Hernández Vara, Jorge Jaumà, Serge Martí Domènech, Ma. Josep Pagonabarraga, Javier Pastor, Pau Planellas, Lluís Pont Sunyer, Claustre Puente, Victor Pujol, Montserrat Saura Martí, Josep Tolosa, Eduardo Valldeoriola Serra, Francesc |
Keywords: | Malaltia de Parkinson Genètica mèdica Expressió gènica Hipocamp (Cervell) Parkinson's disease Medical genetics Gene expression Hippocampus (Brain) |
Issue Date: | 15-Nov-2017 |
Publisher: | Oxford University Press |
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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1093/nar/gkx1048 |
It is part of: | Nucleic Acids Research, 2017, vol. 45, num. 22, p. 12888-12903 |
URI: | http://hdl.handle.net/2445/120734 |
Related resource: | https://doi.org/10.1093/nar/gkx1048 |
ISSN: | 0305-1048 |
Appears in Collections: | Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Biomedicina) |
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