Mice Treated Subcutaneously with Mouse LPS-Converted PrPres or LPS Alone Showed Brain Gene Expression Profiles Characteristic of Prion Disease

Dagnachew Hailemariam,Seyed Ali Goldansaz,Nathalie Daude,Burim N Ametaj,David S Wishart

doi:10.3390/vetsci8090200

Dagnachew Hailemariam, Seyed Ali Goldansaz + Show 3 more

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https://doi.org/10.3390/vetsci8090200

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Journal: Veterinary sciences	Publication Date: Sep 21, 2021
Citations: 1	License type: CC BY 4.0

Affiliation: University of Alberta

Abstract

Previously, we showed that bacterial lipopolysaccharide (LPS) converts mouse PrPC protein to a beta-rich isoform (moPrPres) resistant to proteinase K. In this study, we aimed to test if the LPS-converted PrPres is infectious and alters the expression of genes related to prion pathology in brains of terminally sick mice. Ninety female FVB/N mice at 5 weeks of age were randomly assigned to 6 groups treated subcutaneously (sc) for 6 weeks either with: (1) Saline (CTR); (2) LPS from Escherichia coli 0111:B4 (LPS), (3) one-time sc administration of de novo generated mouse recombinant prion protein (moPrP; 29-232) rich in beta-sheet by incubation with LPS (moPrPres), (4) LPS plus one-time sc injection of moPrPres, (5) one-time sc injection of brain homogenate from Rocky Mountain Lab (RLM) scrapie strain, and (6) LPS plus one-time sc injection of RML. Results showed that all treatments altered the expression of various genes related to prion disease and neuroinflammation starting at 11 weeks post-infection and more profoundly at the terminal stage. In conclusion, sc administration of de novo generated moPrPres, LPS, and a combination of moPrPres with LPS were able to alter the expression of multiple genes typical of prion pathology and inflammation.

Highlights

Transmissible spongiform encephalopathies (TSEs), or prion diseases are a group of fatal neurodegenerative disorders that are characterized by misfolding of cellular prion protein (PrPC ) into a pathogenic form, the scrapie prion protein (PrPSc )
We tested the hypothesis that the moPrPres, administered once sc, would cause prion disease in FVB/N female mice and alter the expression of genes related to prion disease and inflammation in the brain of mice as early as 11 weeks pi and terminal stage
The mRNA expression of genes related to prion disease and inflammation at 11 weeks pi were analyzed in all treatment groups including LPS, moPrPres, RML, and combinations of LPS treated groups in the brain tissue (Table 1)

Summary

Introduction

Transmissible spongiform encephalopathies (TSEs), or prion diseases are a group of fatal neurodegenerative disorders that are characterized by misfolding of cellular prion protein (PrPC ) into a pathogenic form, the scrapie prion protein (PrPSc ). The scrapie or the misfolded form of the protein is commonly found in the brain tissue of affected animals and humans. This led to the development of the prion-only hypothesis [1]. The main challenge for the scientific community was to prove that the misfolded protein (PrPSc ) was the real causative agent of prion disease. There is one drawback of all the reported investigations: they have used un-natural conditions to generate the infectious prions like serial rounds of protein misfolding cyclic amplification (PMCA) and long incubations periods, presence of RNA or other synthetic forms like polyriboadenylic acid, poly-anions like glucosaminoglycans (GAGs), denaturing acidic conditions, and synthetic lipids like

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