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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, Maria 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.
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It is part of: Nucleic Acids Research, 2017, vol. 45, num. 22, p. 12888-12903
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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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