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

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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Marchese D,Botta-Orfila T,Cirillo D,Rodriguez JA,Livi CM,Fernández-Santiago R,Ezquerra M,Martí MJ,Bechara E,Tartaglia GG,Catalan MSA Registry (CMSAR).

doi

10.1093/nar/gkx1048

subject

Has Abstract

pub_date

2017-12-15 00:00:00

pages

12888-12903

issue

22

eissn

0305-1048

issn

1362-4962

pii

4628128

journal_volume

45

pub_type

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