Caprine PRNP Polymorphisms N146S and Q222K Are Associated with Proteolytic Cleavage of PrP

Overview

Journal Genet Sel Evol

Publisher Biomed Central

Specialties Biology
Genetics

Date 2021 Jun 20

PMID 34147084

Citations 1

Authors

Sally A Madsen-Bouterse

Paula Stewart

Helen Williamson

David A Schneider

Wilfred Goldmann

Affiliations

Soon will be listed here.

Abstract

Expression of the cellular prion protein (PrP) is crucial for the development of prion diseases. Amino acid changes in PrP or a reduced amount of PrP may modulate disease resistance. The relative abundance of C1, a natural α-cleavage fragment of PrP, 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 PrP in goats for the existence of similar associations between PrP 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 PrP. The presence of K or S 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.

Citing Articles

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References

ORourke K, Baszler T, Besser T, Miller J, Cutlip R, Wells G . Preclinical diagnosis of scrapie by immunohistochemistry of third eyelid lymphoid tissue. J Clin Microbiol. 2000; 38(9):3254-9. PMC: 87369. DOI: 10.1128/JCM.38.9.3254-3259.2000. View

Cinar M, Schneider D, Waldron D, ORourke K, White S . Goats singly heterozygous for PRNP S146 or K222 orally inoculated with classical scrapie at birth show no disease at ages well beyond 6 years. Vet J. 2018; 233:19-24. DOI: 10.1016/j.tvjl.2017.12.019. View

Campbell L, Gill A, McGovern G, Jalland C, Hopkins J, Tranulis M . The PrP(C) C1 fragment derived from the ovine A136R154R171PRNP allele is highly abundant in sheep brain and inhibits fibrillisation of full-length PrP(C) protein in vitro. Biochim Biophys Acta. 2013; 1832(6):826-36. DOI: 10.1016/j.bbadis.2013.02.020. View

Jeffrey M, Gonzalez L . Classical sheep transmissible spongiform encephalopathies: pathogenesis, pathological phenotypes and clinical disease. Neuropathol Appl Neurobiol. 2007; 33(4):373-94. DOI: 10.1111/j.1365-2990.2007.00868.x. View

Castle A, Daude N, Gilch S, Westaway D . Application of high-throughput, capillary-based Western analysis to modulated cleavage of the cellular prion protein. J Biol Chem. 2018; 294(8):2642-2650. PMC: 6393610. DOI: 10.1074/jbc.RA118.006367. View

Linsenmeier L, Altmeppen H, Wetzel S, Mohammadi B, Saftig P, Glatzel M . Diverse functions of the prion protein - Does proteolytic processing hold the key?. Biochim Biophys Acta Mol Cell Res. 2017; 1864(11 Pt B):2128-2137. DOI: 10.1016/j.bbamcr.2017.06.022. View

Acutis P, Martucci F, DAngelo A, Peletto S, Colussi S, Maurella C . Resistance to classical scrapie in experimentally challenged goats carrying mutation K222 of the prion protein gene. Vet Res. 2012; 43:8. PMC: 3296670. DOI: 10.1186/1297-9716-43-8. View

ORourke K, Baszler T, Miller J, Spraker T, Knowles D . Monoclonal antibody F89/160.1.5 defines a conserved epitope on the ruminant prion protein. J Clin Microbiol. 1998; 36(6):1750-5. PMC: 104913. DOI: 10.1128/JCM.36.6.1750-1755.1998. View

Madsen-Bouterse S, Schneider D, Dassanayake R, Truscott T, Zhuang D, Kumpula-McWhirter N . PRNP variants in goats reduce sensitivity of detection of PrP(Sc) by immunoassay. J Vet Diagn Invest. 2015; 27(3):332-43. DOI: 10.1177/1040638715585865. View

10.

Lewis V, Hill A, Haigh C, Klug G, Masters C, Lawson V . Increased proportions of C1 truncated prion protein protect against cellular M1000 prion infection. J Neuropathol Exp Neurol. 2009; 68(10):1125-35. DOI: 10.1097/NEN.0b013e3181b96981. View

11.

White S, Reynolds J, Waldron D, Schneider D, ORourke K . Extended scrapie incubation time in goats singly heterozygous for PRNP S146 or K222. Gene. 2012; 501(1):49-51. DOI: 10.1016/j.gene.2012.03.068. View

12.

Wiseman F, Cancellotti E, Piccardo P, Iremonger K, Boyle A, Brown D . The glycosylation status of PrPC is a key factor in determining transmissible spongiform encephalopathy transmission between species. J Virol. 2015; 89(9):4738-47. PMC: 4403468. DOI: 10.1128/JVI.02296-14. View

13.

Peralta O, Eyestone W . Quantitative and qualitative analysis of cellular prion protein (PrP(C)) expression in bovine somatic tissues. Prion. 2009; 3(3):161-70. PMC: 2802781. DOI: 10.4161/pri.3.3.9772. View

14.

Alverson J, ORourke K, Baszler T . PrPSc accumulation in fetal cotyledons of scrapie-resistant lambs is influenced by fetus location in the uterus. J Gen Virol. 2006; 87(Pt 4):1035-1041. DOI: 10.1099/vir.0.81418-0. View

15.

Acutis P, Bossers A, Priem J, Riina M, Peletto S, Mazza M . Identification of prion protein gene polymorphisms in goats from Italian scrapie outbreaks. J Gen Virol. 2006; 87(Pt 4):1029-1033. DOI: 10.1099/vir.0.81440-0. View

16.

Papasavva-Stylianou P, Kleanthous M, Toumazos P, Mavrikiou P, Loucaides P . Novel polymorphisms at codons 146 and 151 in the prion protein gene of Cyprus goats, and their association with natural scrapie. Vet J. 2005; 173(2):459-62. DOI: 10.1016/j.tvjl.2005.09.013. View

17.

Beland M, Motard J, Barbarin A, Roucou X . PrP(C) homodimerization stimulates the production of PrPC cleaved fragments PrPN1 and PrPC1. J Neurosci. 2012; 32(38):13255-63. PMC: 6621480. DOI: 10.1523/JNEUROSCI.2236-12.2012. View

18.

Mazza M, Guglielmetti C, Pagano M, Sciuto S, Ingravalle F, Martucci F . Lysine at position 222 of the goat prion protein inhibits the binding of monoclonal antibody F99/97.6.1. J Vet Diagn Invest. 2012; 24(5):971-5. DOI: 10.1177/1040638712457352. View

19.

Westergard L, Turnbaugh J, Harris D . A naturally occurring C-terminal fragment of the prion protein (PrP) delays disease and acts as a dominant-negative inhibitor of PrPSc formation. J Biol Chem. 2011; 286(51):44234-44242. PMC: 3243553. DOI: 10.1074/jbc.M111.286195. View

20.

Castle A, Gill A . Physiological Functions of the Cellular Prion Protein. Front Mol Biosci. 2017; 4:19. PMC: 5382174. DOI: 10.3389/fmolb.2017.00019. View