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Mol Neurobiol. 2018 Mar;55(3):2384-2396. doi: 10.1007/s12035-017-0495-5. Epub 2017 Mar 29.

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

Author information

1
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada.
2
Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, AB, Canada.
3
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada.
4
Department of Infectious Diseases, College of Veterinary Medicine, BK21 PLUS, Seoul National University, Seoul, 08826, Republic of Korea. yoohs@snu.ac.kr.
5
Centre for Prions and Protein Folding Diseases, University of Alberta, Edmonton, AB, Canada. debbie.mckenzie@ualberta.ca.
6
Department of Biological Sciences, University of Alberta, Edmonton, AB, Canada. debbie.mckenzie@ualberta.ca.

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.

KEYWORDS:

Differentiated C2C12 cells; Immune stimulator; Neuronal and glial cells; Prion disease; Therapeutic RNAi

PMID:
28357807
DOI:
10.1007/s12035-017-0495-5
[Indexed for MEDLINE]

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