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Dual MicroRNA to Cellular Prion Protein Inhibits Propagation of Pathogenic Prion Protein in Cultured Cells

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Abstract

Prion diseases are fatal transmissible neurodegenerative disorders affecting humans and various mammals. In spite of intensive efforts, there is no effective cure or treatment for prion diseases. Cellular forms of prion protein (PrPC) is essential for propagation of abnormal isoforms of prion protein (PrPSc) and pathogenesis. The effect of an artificial dual microRNA (DmiR) on PrPC suppression and resultant inhibition of prion replication was determined using prion-infectible cell cultures: differentiated C2C12 culture and primary mixed neuronal and glial cells culture (MNGC). Processing of DmiR by prion-susceptible myotubes, but not by reserve cells, in differentiated C2C12 culture slowed prion replication, implying an importance of cell type-specific PrPC targeting. In MNGC, reduction of PrPC with DmiR was effective for suppressing prion replication. MNGC lentivirally transduced with non-targeting control miRNAs (scrambled) reduced prion replication at a level similar to that with a synthetic analogue of viral RNA, poly I:C. The results suggest that a synergistic combination of the immunostimulatory RNA duplexes (miRNA) and PrPC silencing with DmiR might augment a therapeutic potential of RNA interference.

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Acknowledgements

The authors thank Dr. David Westaway from Department of Medicine, University of Alberta for advice and critical review of this manuscript. We thank Dr. Yong-Sun Kim from College of Medicine, Hallym University, for providing anti-PrP mAb, 3F10. This work was funded by grants from Alberta Prion Research Institute (APRI). The authors declare no competing financial interests.

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Authors and Affiliations

  1. Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada

    Sang-Gyun Kang, Chiye Kim, Judd Aiken & Debbie McKenzie

  2. Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB, Canada

    Sang-Gyun Kang & Judd Aiken

  3. Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada

    Chiye Kim & Debbie McKenzie

  4. Department of Infectious Diseases, College of Veterinary Medicine, BK21 PLUS, Seoul National University, Seoul, 08826, Republic of Korea

    Han Sang Yoo

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Correspondence to Han Sang Yoo or Debbie McKenzie.

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Kang, SG., Kim, C., Aiken, J. et al. Dual MicroRNA to Cellular Prion Protein Inhibits Propagation of Pathogenic Prion Protein in Cultured Cells. Mol Neurobiol 55, 2384–2396 (2018). https://doi.org/10.1007/s12035-017-0495-5

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