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Genome-Wide Identification of microRNAs Regulating the Human Prion Protein


Pease, Daniel; Scheckel, Claudia; Schaper, Elke; Eckhardt, Valeria; Emmenegger, Marc; Xenarios, Ioannis; Aguzzi, Adriano (2019). Genome-Wide Identification of microRNAs Regulating the Human Prion Protein. Brain Pathology, 29(2):232-244.

Abstract

The cellular prion protein (PrPC ) is best known for its misfolded disease-causing conformer, PrPS c . Because the availability of PrPC 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 PrPC levels through direct or indirect pathways. We probed PrPC 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 PrPC 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 PrPC . Our results show that multiple miRNAs regulate PrPC 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 PrPC as a mediator of Aβ toxicity suggests that its regulation by miRNAs may also impinge on Alzheimer's disease. This article is protected by copyright. All rights reserved

Abstract

The cellular prion protein (PrPC ) is best known for its misfolded disease-causing conformer, PrPS c . Because the availability of PrPC 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 PrPC levels through direct or indirect pathways. We probed PrPC 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 PrPC 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 PrPC . Our results show that multiple miRNAs regulate PrPC 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 PrPC as a mediator of Aβ toxicity suggests that its regulation by miRNAs may also impinge on Alzheimer's disease. This article is protected by copyright. All rights reserved

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Pathology and Forensic Medicine, General Neuroscience, Clinical Neurology
Language:English
Date:1 March 2019
Deposited On:30 Nov 2018 16:49
Last Modified:28 Feb 2020 08:26
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1015-6305
OA Status:Green
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/bpa.12679
PubMed ID:30451334
Project Information:
  • : FunderH2020
  • : Grant ID670958
  • : Project TitleFunction and malfunction of the prion protein
  • : FunderSNSF
  • : Grant ID31003A_179040
  • : Project TitleThe prion protein in health and disease
  • : FunderCRPP
  • : Grant IDSmall RNAs
  • : Project TitleCRPP Small RNAs
  • : Project Websitehttps://www.rna.uzh.ch/en.html
  • : FunderCRPP
  • : Grant IDHHLD
  • : Project TitleHuman Hemato-Lymphatic Diseases
  • : Project Websitehttps://www.hhld.uzh.ch/en.html
  • : FunderSystemsX.ch
  • : Grant ID2014/260
  • : Project TitlePrionX
  • : FunderSPHN
  • : Grant ID2017DRI17
  • : Project TitlePopulation-wide screens of the immune repertoire: a reverse personalized-medicine approach

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