1. Academic Validation
  2. Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model

Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model

  • Mol Neurobiol. 2020 May;57(5):2206-2219. doi: 10.1007/s12035-020-01880-y.
Simrika Thapa  # 1 2 3 Dalia H Abdelaziz  # 1 2 3 4 Basant A Abdulrahman 1 2 3 4 Hermann M Schatzl 5 6 7
Affiliations

Affiliations

  • 1 Calgary Prion Research Unit, University of Calgary, Calgary, Alberta, Canada.
  • 2 Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, TRW 2D10, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada.
  • 3 Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, Alberta, Canada.
  • 4 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
  • 5 Calgary Prion Research Unit, University of Calgary, Calgary, Alberta, Canada. hschaetz@ucalgary.ca.
  • 6 Department of Comparative Biology & Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, TRW 2D10, 3280 Hospital Drive NW, Calgary, Alberta, T2N 4Z6, Canada. hschaetz@ucalgary.ca.
  • 7 Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, Alberta, Canada. hschaetz@ucalgary.ca.
  • # Contributed equally.
Abstract

Prion diseases are fatal infectious neurodegenerative disorders in human and Animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein Phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion Infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.

Keywords

ER stress; Prion; Prion infection; Protein misfolding; Sephin1; UPR.

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