Caprine PRNP polymorphisms N146S and Q222K are associated with proteolytic cleavage of PrPC

Wilfred Goldmann,Sally A. Madsen-Bouterse,Helen Williamson,Paula Stewart,David A. Schneider

doi:10.1186/s12711-021-00646-x

Abstract

Expression of the cellular prion protein (PrPC) is crucial for the development of prion diseases. Amino acid changes in PrPC or a reduced amount of PrPC may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrPC, was previously found to be associated with a resistant PRNP genotype in sheep. Goats are another small ruminant where classical scrapie susceptibility is under strong genetic control. In this study, we assessed PrPC in goats for the existence of similar associations between PrPC fragments and genotype. Brain tissue homogenates from scrapie-free goats with wild type PRNP or polymorphisms (I142M, H143R, N146S, or Q222K) were deglycosylated prior to immunoblot for assessment of the relative abundance of the C1 fragment of PrPC. The presence of K222 or S146 alleles demonstrated significantly different relative levels of C1 compared to that observed in wild type goats, which suggests that the genotype association with C1 is neither unique to sheep nor exclusive to the ovine Q171R dimorphism.

Highlights

Expression of the cellular form of the prion protein (PrPC) is essential for the pathogenesis of a group of disorders called prion diseases, known as transmissible spongiform encephalopathies (TSE)
Of interest in the current study are goat genotypes defined by polymorphisms that result in amino acid changes at codons, 146, and 222
Relative abundance of P rPC C1 fragment in goats with wild type PRNP and genotypes associated with delayed scrapie incubation The brain is the penultimate site of PrPC conversion to PrPSc prior to the development of clinical signs associated with classical scrapie

Summary

Introduction

Expression of the cellular form of the prion protein (PrPC) is essential for the pathogenesis of a group of disorders called prion diseases, known as transmissible spongiform encephalopathies (TSE). Prion diseases are marked by the accumulation of protease-resistant isoforms of the prion protein, designated PrPSc, in the central nervous system [1]. The PrPC bands detected after deglycosylation typically have apparent molecular weights of 26 kDa, 18 kDa and 16 kDa, representing full-length PrPC (209 amino acids) and two shorter fragments generated by proteolytic cleavage ([6] and reviewed in [7, 8]). Of the two shorter fragments, the 16 kDa band represents a 120 amino acid C-terminal fragment (C1) produced by the so-called α-cleavage between histidine114 and valine115. The 18 kDa band represents an approximately 142 amino acid C-terminal fragment (C2) produced by β-cleavage at or near

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