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发现3'非翻译区介导的α-突触核蛋白调控。

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

作者信息

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

机构信息

Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.

Universitat Pompeu Fabra (UPF), Barcelona, Spain.

出版信息

Nucleic Acids Res. 2017 Dec 15;45(22):12888-12903. doi: 10.1093/nar/gkx1048.

DOI:10.1093/nar/gkx1048
PMID:29149290
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5728410/
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.

摘要

最近的证据表明，帕金森病（PD）与具有不同3'非翻译区（3'UTR）的α-突触核蛋白（SNCA）亚型的表达之间存在联系。然而，调节SNCA表达的转录后机制尚不清楚。通过大规模的体外/计算机筛选，我们鉴定了与SNCA 3'UTR相互作用的RNA结合蛋白（RBP）。我们鉴定出两种RBP，即ELAVL1和TIAR，它们与最丰富且具有翻译活性的3'UTR亚型（575 nt）具有高亲和力结合。敲低和过表达实验表明，ELAVL1和TIAR在体内均正向调节内源性SNCA。调节机制意味着mRNA稳定以及TIAR情况下的翻译增强。我们观察到，在帕金森病和多系统萎缩（MSA）患者的死后脑供体运动皮层和原代培养成纤维细胞中，TIAR和ELAVL1的表达均有显著改变。此外，反式表达数量性状基因座（trans-eQTLs）分析表明，TIAR基因组位点中的一组单核苷酸多态性（SNP）影响伏隔核和海马体这两个不同脑区的SNCA表达。我们的研究揭示了3'UTR介导的SNCA调节及其与PD发病机制的联系，从而为神经退行性变中转录后机制的研究开辟了新途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/68d0569925f3/gkx1048fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/643d3a607da5/gkx1048fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/dbddbf5c54f4/gkx1048fig2.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/4a32340c09a6/gkx1048fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/b50ca6c977bd/gkx1048fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/be3d6513d9b5/gkx1048fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/d455c246a154/gkx1048fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/f2d4925bed14/gkx1048fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/68d0569925f3/gkx1048fig9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/643d3a607da5/gkx1048fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/dbddbf5c54f4/gkx1048fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/7a7d4bcba6f5/gkx1048fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/4a32340c09a6/gkx1048fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/b50ca6c977bd/gkx1048fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/be3d6513d9b5/gkx1048fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/d455c246a154/gkx1048fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/f2d4925bed14/gkx1048fig8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/992c/5728410/68d0569925f3/gkx1048fig9.jpg

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