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Genome-wide identification of microRNAs regulating the human prion protein
Daniel Pease1, Claudia Scheckel1, Elke Schaper1,2
1Institute of Neuropathology, University of Zürich, Zürich, Switzerland.
Abstract:
The cellular prion protein (PrPC ) is best known for its misfolded disease-causing conformer, PrPSc . 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.
Insights
Researchers screened microRNAs to understand regulation of the cellular prion protein (PrPC). Multiple microRNAs directly and indirectly control PrPC levels, offering potential therapeutic targets for prion and Alzheimer
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- The cellular prion protein (PrPC) is crucial in prion diseases, and its regulation is key for therapeutic strategies.
- PrPC availability often limits prion propagation, highlighting the need to understand its regulatory mechanisms.
Purpose of the Study:
- To investigate the role of the human microRNAome in modulating PrPC levels.
- To identify specific microRNAs that directly or indirectly regulate PrPC expression.
Main Methods:
- Genome-wide screening of 2019 miRNA mimics using a time-resolved fluorescence-resonance screening assay.
- PrPC protein levels were measured in three human neuroectodermal cell lines (U-251 MG, CHP-212, SH-SY5Y).
- Identification of miRNA binding sites within the PRNP gene (3'UTR and CDS).
Main Results:
- 17 overlapping high-confidence miRNA mimic hits were identified across the three cell lines.
- 13 miRNAs directly regulate PrPC biosynthesis by binding to the PRNP 3'UTR, leading to transcript degradation.
- Four miRNAs (miR-124-3p, 192-3p, 299-5p, 376b-3p) indirectly regulate PrPC without binding the PRNP 3'UTR or CDS.
Conclusions:
- Multiple microRNAs directly and indirectly regulate cellular prion protein (PrPC) levels.
- These findings offer potential therapeutic targets for prion diseases.
- MicroRNA-mediated regulation of PrPC may also impact Alzheimer's disease pathogenesis due to PrPC's role in Aβ toxicity.
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