Discovering the 3' UTR-mediated regulation of alpha-synuclein
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Discovering the 3' UTR-mediated regulation of alpha-synuclein. / Marchese, Domenica; Botta-Orfila, Teresa; Cirillo, Davide; Rodriguez, Juan Antonio; Livi, Carmen Maria; Fernández-Santiago, Rubén; Ezquerra, Mario; Martí, Maria J.; Bechara, Elias; Tartaglia, Gian Gaetano.
In: Nucleic Acids Research, Vol. 45, No. 22, 2017, p. 12888-12903.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Discovering the 3' UTR-mediated regulation of alpha-synuclein
AU - Marchese, Domenica
AU - Botta-Orfila, Teresa
AU - Cirillo, Davide
AU - Rodriguez, Juan Antonio
AU - Livi, Carmen Maria
AU - Fernández-Santiago, Rubén
AU - Ezquerra, Mario
AU - Martí, Maria J.
AU - Bechara, Elias
AU - Tartaglia, Gian Gaetano
N1 - Publisher Copyright: ©.The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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 postmortem 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' UTRmediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.
AB - 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 postmortem 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' UTRmediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.
U2 - 10.1093/nar/gkx1048
DO - 10.1093/nar/gkx1048
M3 - Journal article
C2 - 29149290
AN - SCOPUS:85040610942
VL - 45
SP - 12888
EP - 12903
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 22
ER -
ID: 327323348