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

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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.

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Acknowledgments

We would like to thank our animal care technicians, Dr. Lillian Oribhabor and Bukola Alli, for their excellent support in animal husbandry and care. We also would like to thank Lauren Vankuppeveld for her help in cell culture-related work. We are also thankful to Yo-Ching Cheng for preparing the recombinant mouse PrP substrate used in RT-QuIC assay.

Funding

This work was performed within the framework of the Calgary Prion Research Unit and was supported by grants from Alberta Innovates/Alberta Prion Research Institute (APRI grant 201600010). ST is a University of Calgary Eyes High, Killam doctoral, and Alberta Innovates Health Solution (AIHS)-Health doctoral fellow. DHA was a University of Calgary Eyes High postdoctoral fellow; BAA was an AIHS postdoctoral fellow.

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  1. Simrika Thapa and Dalia H. Abdelaziz contributed equally to this work.

Authors and Affiliations

  1. Calgary Prion Research Unit, University of Calgary, Calgary, Alberta, Canada

    Simrika Thapa, Dalia H. Abdelaziz, Basant A. Abdulrahman & Hermann M. Schatzl

  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

    Simrika Thapa, Dalia H. Abdelaziz, Basant A. Abdulrahman & Hermann M. Schatzl

  3. Hotchkiss Brain Institute (HBI), University of Calgary, Calgary, Alberta, Canada

    Simrika Thapa, Dalia H. Abdelaziz, Basant A. Abdulrahman & Hermann M. Schatzl

  4. Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Helwan University, Cairo, Egypt

    Dalia H. Abdelaziz & Basant A. Abdulrahman

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  1. Simrika Thapa
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Contributions

ST, DHA, and HMS designed the experiments. ST, DHA, and BAA conducted the experiments. ST and DHA performed the animal experiments. ST and HMS wrote the manuscript. The manuscript was revised and approved by all authors.

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Correspondence to Hermann M. Schatzl.

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Thapa, S., Abdelaziz, D.H., Abdulrahman, B.A. et al. Sephin1 Reduces Prion Infection in Prion-Infected Cells and Animal Model. Mol Neurobiol 57, 2206–2219 (2020). https://doi.org/10.1007/s12035-020-01880-y

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