Genome-wide identification of microRNAs regulating the human prion protein.

Détails

ID Serval
serval:BIB_D8AA7D2C9603
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Genome-wide identification of microRNAs regulating the human prion protein.
Périodique
Brain pathology
Auteur(s)
Pease D., Scheckel C., Schaper E., Eckhardt V., Emmenegger M., Xenarios I., Aguzzi A.
ISSN
1750-3639 (Electronic)
ISSN-L
1015-6305
Statut éditorial
Publié
Date de publication
03/2019
Peer-reviewed
Oui
Volume
29
Numéro
2
Pages
232-244
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
The cellular prion protein (PrP <sup>C</sup> ) is best known for its misfolded disease-causing conformer, PrP <sup>Sc</sup> . Because the availability of PrP <sup>C</sup> is often limiting for prion propagation, understanding its regulation may point to possible therapeutic targets. We sought to determine to what extent the human microRNAome is involved in modulating PrP <sup>C</sup> levels through direct or indirect pathways. We probed PrP <sup>C</sup> protein levels in cells subjected to a genome-wide library encompassing 2019 miRNA mimics using a robust time-resolved fluorescence-resonance screening assay. Screening was performed in three human neuroectodermal cell lines: U-251 MG, CHP-212 and SH-SY5Y. The three screens yielded 17 overlapping high-confidence miRNA mimic hits, 13 of which were found to regulate PrP <sup>C</sup> biosynthesis directly via binding to the PRNP 3'UTR, thereby inducing transcript degradation. The four remaining hits (miR-124-3p, 192-3p, 299-5p and 376b-3p) did not bind either the 3'UTR or CDS of PRNP, and were therefore deemed indirect regulators of PrP <sup>C</sup> . Our results show that multiple miRNAs regulate PrP <sup>C</sup> levels both directly and indirectly. These findings may have profound implications for prion disease pathogenesis and potentially also for their therapy. Furthermore, the possible role of PrP <sup>C</sup> as a mediator of Aβ toxicity suggests that its regulation by miRNAs may also impinge on Alzheimer's disease.
Mots-clé
3' Untranslated Regions/genetics, Alzheimer Disease, Cell Line, Genome-Wide Association Study/methods, Humans, MicroRNAs/genetics, MicroRNAs/physiology, PrPC Proteins/genetics, PrPC Proteins/metabolism, Prion Diseases/genetics, Prion Proteins/genetics, Prions/genetics, Protein Binding/genetics, 3'UTR, PRNP, PrP, microRNA, screen
Pubmed
Web of science
Création de la notice
26/11/2018 14:50
Dernière modification de la notice
16/09/2019 6:26
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