Development & Reproduction
Korean Society of Developmental Biology
Review article

Physiology of Cellular Prion Proteins in Reproduction

Željko M. Svedružić1https://orcid.org/0000-0002-0736-6182, Chongsuk Ryou2https://orcid.org/0000-0001-8363-1059, Donchan Choi3https://orcid.org/0000-0002-5170-090X, Sung-Ho Lee4https://orcid.org/0000-0003-2866-3642, Yong-Pil Cheon†,5https://orcid.org/0000-0002-8497-9257
1Department of Biotechnology, University of Rijeka, 51000 Rijeka, Croatia
2Department of Pharmacy, College of Pharmacy, Hanyang University ERICA, Ansan 15588, Korea
3Department Life Science, College of Health Science and Welfare, Yong-In University, Yongin 17092, Korea
4Department of Biotechnology, Sangmyung University, Seoul 03016, Korea
5Division of Developmental Biology and Physiology, Department of Biotechnology, Institute for Basic Sciences, Sungshin University, Seoul 02844, Korea
Corresponding author Yong-Pil Cheon, Division of Developmental Biology and Physiology, Department of Biotechnology, Institute for Basic Sciences, Sungshin University, Seoul 02844, Korea, Tel: +82-2-920-7639, Fax: +82-2-920-2736, E-mail: ypcheon@sungshin.ac.kr

© Copyright 2024 The Korean Society of Developmental Biology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received: Mar 13, 2024 ; Revised: Mar 25, 2024 ; Accepted: Mar 30, 2024

Published Online: Jun 30, 2024

Abstract

Cellular prion protein (PrPC) encoded at Prnp gene is well-known to form a misfolded isoform, termed scrapie PrP (PrPSC) that cause transmissible degenerative diseases in central nervous system. The physiological role of PrPC has been proposed by many studies, showing that PrPC interacts with various intracellular, membrane, and extracellular molecules including mitochondrial inner membrane as a scaffold. PrPC is expressed in most cell types including reproductive organs. Numerous studies using PrPC knockout rodent models found no obvious phenotypic changes, in particular the clear phenotypes in development and reproduction have not demonstrated in these knockout models. However, various roles of PrPC have been evaluated at the cellular levels. In this review, we summarized the known roles of PrPC in various cell types and tissues with a special emphasis on those involved in reproduction.

Keywords: Cellular prion protein; Reproduction; Knockout; Scrapie PrP; Scaffold

INTRODUCTION

Cellular prion protein (PrPC) has been mostly focused by its misfolded, disease-associated scrapie prion protein (PrPSC) that causes transmissible degenerative conditions in the central nervous system known as prion diseases (Gilch & Schatzl, 2023). PrPSC that largely composes the prion pathogen aggregates by themselves and becomes amyloids (Prusiner, 1991). Besides the pathophysiology of PrPSC, the studies to understand the physiological roles of PrPC are emphasized recently.

PrPC is a ubiquitous glycoprotein, which is present in almost all cell types (Bendheim et al., 1992; Castle & Gill, 2017; unpublished data in Cheon’s Lab). PrPC is localized in lipid raft membrane domains enriched in phosphatidylinositols, ceramides, cholesterol, and sphingolipids (such as GM3, GM1 and GD3) microdomains through glycosylphosphatidylinositol (GPI) anchor on the extracellular side (Walsh et al., 2014; Mattei et al., 2015). PrPC is encoded in a Prnp gene on chromosome 20 in human and 2 in mouse, and is conserved throughout vertebrates (Vanderperre et al., 2011). It is known that Prnp gene is expressed by the result of various stimuli including steroid hormones (Bravard et al., 2015; Peng et al., 2022). Mature PrPC contains five octapeptide repeats in N-terminal, a hydrophobic domain in the middle, and a globular domain with three α-helices and two stranded antiparallel β-sheets in C-terminal regions (Walmsley et al., 2001; Béland & Roucou, 2012).

PrPC can work as receptor and scaffold for various molecules and its role is not exclusively limited to the nervous system (Aguzzi et al., 2008). It is suggested that PrPC forms dimer in native conditions and dimerization may be involved in cellular signaling (Roucou, 2014). The physiological roles of PrPC can be reasoned through its interacting molecules, and they are context- and cell-dependent (Linden, 2017; Kovač & Čurin Šerbec, 2022). It is revealed that PrPC can interact with various intracellular and extracellular molecules.

So far, many studies have evaluated the possible roles of PrPC and its related conformation changes. However, the possible roles of PrPC are mostly undefined in reproduction, although it is suspected that PrPC might have many cellular functions. So, in here we review the previous studies and introduce the possible roles of PrPC in reproduction.

GENERAL FUNCTION OF PrPC

PrPC expresses universally from gamete to differentiated cell and interacts with intracellular proteins (Nandi, 1997). Besides, it involves signal transduction through interaction with extracellular proteins and plasma membrane proteins (Hajj et al., 2007). In cell-to-cell communication, PrPC works as a scaffold. Caveolae, a platform for signal transduction, is the location for PrPC and it works as a scaffold for signaling modules (Linden, 2017; Martellucci et al., 2020). PrPC signaling mediation is depending on the binding partners. The known signaling pathways are including follows: Erk1/2 phosphorylation (Isaacs et al., 2006; Caetano et al., 2008), Ras-Raf cascade (Pantera et al., 2009), Wnt-β-catenin cascade (Besnier et al., 2015), Src-related kinase (Málaga-Trillo et al., 2009), etc. On the other hand, PrPC is also involved in intercellular communication. PrPC is transported via exosomes and plays many roles according to its localization (Budnik et al. 2016; Sigurdson et al., 2019; lves et al., 2020). It also works in pathophysiology and becomes a way of prion spread of prion (Sigurdson et al., 2019).

In concerned with histology, PrPC is involved in cell-to-cell adhesion through trafficking of E-cadherin (Iglesia et al., 2017). PrPC interacts with junctional proteins such as desmosomal adhesion junctional proteins and tight junctional proteins (Megra et al., 2018). It also interacts with various extracellular matrix molecules including stress-inducible protein-1 and laminin (Hajj et al., 2007). In Prnp knockout mice the levels of adhesion molecules are decreased (Petit et al., 2012) and in epithelium-specific Prnp knockout mice the paracellular permeability is increased (Sarnataro et al., 2016). On the other hand, PrPC regulates the cellular structure either as a regulator or as an interacting molecule (Schmitz et al., 2014). The levels of several PrPC binding cytoskeletal proteins such as intermediary filaments, neurofilament heavy chain, spectrin and vimentin are different in Prnp knockout mice (Schmitz et al., 2014). Suppression of PrPC in pancreatic ductal adenocarcinoma cell line alters the cytoskeleton (Li et al., 2009).

In cellular physiology, ion homeostasis such as Ca2+ and Cu2+ is regulated by PrPC (Castle & Gill, 2017). Plasma membrane bound PrPC tunes Ca2+ transients in the cytosol and mitochondrial matrix (De Mario et al, 2019). Cu2+ homeostasis in mitochondria is regulated by PrPC through bidirectional trafficking of Ca2+ (Faris et al., 2017). In intracellular transport, PrPC is involved through forming a complex with muskelin, dynein and IF5C at transport vesicle (Heisler et al., 2018). It also suggested that PrPC may be involved in energy balance, metabolism, and gene expression. PrPC promotes glucose uptake through glucose transporter 1 mediated by Fyn-hypoxia-inducible factor-2α pathway (Li et al., 2011). It also has been known that PrPC involves in nucleic acid metabolism (Strom et al., 2006), controlling in gene expression through miRNA (Gibbings et al., 2012), and working as histone modifiers and chromatin remodeler (Chakrabortee et al., 2016).

PrPC is also involved in survivability and immunity in tissues. For example, interactions of PrPC with ER mitochondria-associated membrane and microtubule network release the cytochrome c (Sorice et al., 2012; Faris et al., 2017). On the other hand, it’s well known role is protection of the cells from various toxic stimuli and death (Abi Nahed et al., 2023). Intracellular PrPC interacts with BCL2 and blocks the conformational changes of BAX (Abi Nahed et al., 2023). In the immune system, PrPC is a player in immunological quiescence (Bakkebø et al., 2015). In Prnp knockout mice, the expression level of IL-10 is less than wild type (Liu et al., 2015).

Recently, it emerged that PrPC is involved in various disease such as cancer and Alzheimer’s disease. The high level of PrPC drives the proliferation in cancer cells and growth the xenografted tumor via PI3/AKT signaling pathway and cyclin D expression in a cancer cell type-dependent manner (Liang et al., 2007; Limone et al., 2023). PrPC interacts with various Alzheimer’s disease-related proteins such as amyloid-β oligomers (AβO) which accumulation is cause of an early toxic event (Dohler et al., 2014).

REPRODUCTION

During development the expression of Prnp is detected from early stage embryos to matured organs as a well conserved gene. The function of PrPC is suspected to be compensated by its family gene products and not indispensable one. However, the possible roles of PrPC have been revealed from the study of cell levels. The possible roles of PrPC in reproductive cells have been summarized through some review papers (Miranda et al., 2013). PrPC expresses in the reproductive tracts and gonads such as ovary, testis, oviduct, uterine endometrium, myometrium, maternal-/fetal-placenta, follicle, and granulosa cells in mammals including bovine and ovine (Tuo et al., 2001; Thumdee et al., 2007).

Interestingly, it seems like that the Prnp is not essential in gametogenesis because the knockout male and female mice are fertile without showing histological changes. Moreover, Prnp polymorpism does not affect on reproduction (Gruszecki et al., 2012), although Prnp expression is detected in gonad. Recently, we have developed a few genetically modified mice line that express either a transpene or a knock-in (KI) construct of Prnp gene. Interestingly, these model mice also showed normal reproduction with the same litter size in both male and female (unpublished data in Cheon’s Lab). In fact, previous studies showed that the expression patterns of Prnp are dependent on the species. In male mice gonads, Prnp expression is restricted to spermatogonia, spermatocytes, round spermatids, and Sertoli cells. 2.2 kb Prnp transcript is present in testis at all ages, and 1.1 kb transcript in testis of mice older than two weeks (Fujisawa et al., 2004). The complete and truncated (C- or N-terminally) PrPC are secreted by the epididymal epithelium (Gatti et al., 2002) and are present in hydrophobic membrane vesicle, epididymosomes and in soluble form in epididymal fluid of the ram (Ecroyd et al., 2004). Functional PrPC is localized in the sperm membrane raft domains (Ecroyd et al., 2004), suggesting a possibility of a protective role to stress for copper toxicity (Shaked et al., 1999). Consistently, the superoxide dismutase and catalase activity is decreased and suggest the antioxidant function in the whole organism (Klamt et al., 2001). On the other hand, it is suggested that the high expression level of Prnp in Sertoli cells supports the development of spermatogonial stem cells (Johnston et al., 2008).

In female reproduction, one of the possible roles of PrPC is the maintenance of dominance of the selected dominant follicle during folliculogenesis. The levels of Prnp are higher in the theca cell of the dominant follicles compared to other stages of follicles but not in granulosa cells (Forde et al., 2008). In mRNA level, the expression of Prnp is detected in oocyte in cattle and sheep (Thumdee et al., 2007). In our study, the expression of Prnp is detected in oocyte and early stage embryos (Cheon’ Lab unpublished data).

In uterus, it is suggested that PrPC play a certain role during implantation and decidualization. The Prnp expression is detected in spatiotemporal manner during early pregnancy. PrPC is highly localized in decidual zone at the implantation window stage responding to the embryo implantation (Ding et al., 2018). E2 stimulation up-regulates PrPC expression in endometrial stromal cells and PrPC promotes the proliferative, migratory and invasive abilities of endometrial stromal cells. PrPC promotes cholesterol accumulation and activates estrogen biosynthesis of endometrial stromal cells in a PPARα pathway-dependent manner (Peng et al., 2022). E2 treatment of ovariectomized (OVX) ewes increases the expression of Prnp mRNA and protein in uterus. PrPC is localized at the stromal cells of deep intercaruncular areas of nonpregnant uterus (Johnson et al., 2014). In placenta, Prnp mRNA is localized to a subpopulation of decidual cells (Tanji et al., 1995). PrPC is immunolocalized in the flattened luminal epithelial cells apposed to the fetal membranes (Johnson et al., 2014).

Although Prnp null mice are fertile, the Prnp family genes show an effect on fertility. Prnd and Prnt is considered as a testis-specific protein. Prnd gene, aa homolog of Prnp, is located near the Prnp and its product Doppel (Dpl) has a high homolog with Prnp product PrPC in biochemistry and structure. Dpl expresses in Sertoli cells and at the late stages of spermatogenesis. Dpl-deficient male mice are sterile with the decreased number of spermatids and defection in sperm-egg interaction (129/ola genetic background) (Behrens et al., 2002; Allais-Bonnet & Pailhoux, 2014) or the altered chromatin structure and DNA damage in the sperm (C57BL6/CBA genetic background) (Paisley et al., 2004). However, Dpl null female mice is fertile (Allais-Bonnet & Pailhoux, 2014). On the other hand, in human, Prnt, another Prnp homolog, is expressed in adult testis, suggesting the role in sperm freezability (Makrinou et al., 2002; Pereira et al., 2018).

CONCLUSION

PrPC is localized in cellular organelles and membrane of numerous type of tissues (including reproductive organs, embryo, and solid tumors), and it can be transported by secretion and exosome. So far, the phenotypes are not strict in reproduction in knockout and mutant mice of Prnp gene. However, many different physiological changes have been evaluated in knockout or mutant cells. Recent studies show the antagonistic or compensation actions between prion family Various molecules are identified as a binding molecule of PrPC and the possible roles of PrPC depend on its partners. In male and female, the gametogenesis is not affected by the PrPC and sperm and egg have normal competence and fertilization ability and forming a normal offspring. Although the further studies to understand the possible roles of PrPC in reproduction will be provided in the future, so far, the Prnp products are not essential by its own existence in mammals, but its family gene products are.

Conflict of interests

The authors declare no potential conflict of interest.

Acknowledgements

This work was supported by National Research Foundation of Korea (NRF)-2021K1A4A7A02098794 and 2023R1A2C3007223121.

Authors’ contributions

Conceptualization: Cheon YP, Svedružić ZM.

Writing-original draft: Cheon YP.

Writing-review & editing: Svedružić ZM, Ryou C, Choi D, Lee SH, Cheon YP.

Ethics approval

This article does not require IRB/IACUC approval because there are no human and animal participants.

REFERENCES

1.

Abi Nahed R, Safwan-Zaiter H, Gemy K, Lyko C, Boudaud M, Desseux M, Marquette C, Barjat T, Alfaidy N, Benharouga M. 2023; The multifaceted functions of prion protein (PrPC) in cancer. Cancers (Basel). 15:4982

2.

Aguzzi A, Baumann F, Bremer J. 2008; The prion’s elusive reason for being. Annu Rev Neurosci. 31:439-477

3.

Allais-Bonnet A, Pailhoux E. 2014; Role of the prion protein family in the gonads. Front Cell Dev Biol. 2:56

4.

Alves RN, Iglesia RP, Prado MB, Melo Escobar MI, Boccacino JM, Fernandes CFL, Coelho BP, Fortes AC, Lopes MH. 2020; A new take on prion protein dynamics in cellular trafficking. Int J Mol Sci. 21:7763

5.

Bakkebø MK, Mouillet-Richard S, Espenes A, Goldmann W, Tatzelt J, Tranulis MA. 2015; The cellular prion protein: A player in immunological quiescence. Front Immunol. 6:450

6.

Behrens A, Genoud N, Naumann H, Rülicke T, Janett F, Heppner FL, Ledermann B, Aguzzi A. 2002; Absence of the prion protein homologue Doppel causes male sterility. EMBO J. 21:3652-3658

7.

Béland M, Roucou X. 2012; The prion protein unstructured N-terminal region is a broad-spectrum molecular sensor with diverse and contrasting potential functions. J Neurochem. 120:853-868

8.

Bendheim PE, Brown HR, Rudelli RD, Scala LJ, Goller NL, Wen GY, Kascsak RJ, Cashman NR, Bolton DC. 1992; Nearly ubiquitous tissue distribution of the scrapie agent precursor protein. Neurology. 42:149-156

9.

Besnier LS, Cardot P, Da Rocha B, Simon A, Loew D, Klein C, Riveau B, Lacasa M, Clair C, Rousset M, Thenet S. 2015; The cellular prion protein PrPC is a partner of the Wnt pathway in intestinal epithelial cells. Mol Biol Cell. 26:3313-3328

10.

Bravard A, Auvré F, Fantini D, Bernardino-Sgherri J, Sissoëff L, Daynac M, Xu Z, Etienne O, Dehen C, Comoy E, Boussin FD, Tell G, Deslys JP, Radicella JP. 2015; The prion protein is critical for DNA repair and cell survival after genotoxic stress. Nucleic Acids Res. 43:904-916

11.

Budnik V, Ruiz-Cañada C, Wendler F. 2016; Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci. 17:160-172

12.

Caetano FA, Lopes MH, Hajj GN, Machado CF, Pinto Arantes C, Magalhães AC, Vieira Mde P, Américo TA, Massensini AR, Priola SA, Vorberg I, Gomez MV, Linden R, Prado VF, Martins VR, Prado MA. 2008; Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1. J Neurosci. 28:6691-6702

13.

Castle AR, Gill AC. 2017; Physiological functions of the cellular prion protein. Front Mol Biosci. 4:19

14.

Chakrabortee S, Kayatekin C, Newby GA, Mendillo ML, Lancaster A, Lindquist S. 2016; Luminidependens (LD) is an Arabidopsis protein with prion behavior. Proc Natl Acad Sci USA. 113:6065-6070

15.

De Mario A, Peggion C, Massimino ML, Norante RP, Zulian A, Bertoli A, Sorgato MC. 2019; The link of the prion protein with Ca2+ metabolism and ROS production, and the possible implication in Aβ toxicity. Int J Mol Sci. 20:4640

16.

Ding NZ, Wang XM, Jiao XW, Li R, Zeng C, Li SN, Guo HS, Wang ZY, Huang Z, He CQ. 2018; Cellular prion protein is involved in decidualization of mouse uterus. Biol Reprod. 99:319-325

17.

Dohler F, Sepulveda-Falla D, Krasemann S, Altmeppen H, Schlüter H, Hildebrand D, Zerr I, Matschke J, Glatzel M. 2014; High molecular mass assemblies of amyloid-β oligomers bind prion protein in patients with Alzheimer’s disease. Brain. 137:873-886

18.

Ecroyd H, Sarradin P, Dacheux JL, Gatti JL. 2004; Compartmentalization of prion isoforms within the reproductive tract of the ram. Biol Reprod. 71:993-1001

19.

Faris R, Moore RA, Ward A, Race B, Dorward DW, Hollister JR, Fischer ER, Priola SA. 2017; Cellular prion protein is present in mitochondria of healthy mice. Sci Rep. 7:41556

20.

Forde N, Rogers M, Canty MJ, Lonergan P, Smith GW, Coussens PM, Ireland JJ, Evans AC. 2008; Association of the prion protein and its expression with ovarian follicle development in cattle. Mol Reprod Dev. 75:243-249

21.

Fujisawa M, Kanai Y, Nam SY, Maeda S, Nakamuta N, Kano K, Kurohmaru M, Hayashi Y. 2004; Expression of Prnp mRNA (prion protein gene) in mouse spermatogenic cells. J Reprod Dev. 50:565-570

22.

Gatti JL, Métayer S, Moudjou M, Andréoletti O, Lantier F, Dacheux JL, Sarradin P. 2002; Prion protein is secreted in soluble forms in the epididymal fluid and proteolytically processed and transported in seminal plasma. Biol Reprod. 67:393-400

23.

Gibbings D, Leblanc P, Jay F, Pontier D, Michel F, Schwab Y, Alais S, Lagrange T, Voinnet O. 2012; Human prion protein binds Argonaute and promotes accumulation of microRNA effector complexes. Nat Struct Mol Biol. 19:517-524

24.

Gilch S, Schätzl HM. 2023; New developments in prion disease research. Cell Tissue Res. 392:1-5

25.

Gruszecki TM, Greguta-Kania M, Niznikowski R, Pieta M, Kostro K, Szymanowska A, Miduch A, Strzelec E. 2012; Effect of PRNP gene polymorphism on reproductive performance of mother sheep and their ofspring growth. Bull Vet Inst Pulawy. 56:279-282

26.

Hajj GN, Lopes MH, Mercadante AF, Veiga SS, da Silveira RB, Santos TG, Ribeiro KC, Juliano MA, Jacchieri SG, Zanata SM, Martins VR. 2007; Cellular prion protein interaction with vitronectin supports axonal growth and is compensated by integrins. J Cell Sci. 120:1915-1926

27.

Heisler FF, Pechmann Y, Wieser I, Altmeppen HC, Veenendaal L, Muhia M, Schweizer M, Glatzel M, Krasemann S, Kneussel M. 2018; Muskelin coordinates PrPC lysosome versus exosome targeting and impacts prion disease progression. Neuron. 99:1155-1169

28.

Iglesia RP, Prado MB, Cruz L, Martins VR, Santos TG, Lopes MH. 2017; Engagement of cellular prion protein with the co-chaperone Hsp70/90 organizing protein regulates the proliferation of glioblastoma stem-like cells. Stem Cell Res Ther. 8:76

29.

Isaacs JD, Jackson GS, Altmann DM. 2006; The role of the cellular prion protein in the immune system. Clin Exp Immunol. 146:1-8

30.

Johnston DS, Wright WW, Dicandeloro P, Wilson E, Kopf GS, Jelinsky SA. 2008; Stage-specific gene expression is a fundamental characteristic of rat spermatogenic cells and Sertoli cells. Proc Natl Acad Sci USA. 105:8315-8320

31.

Johnson ML, Grazul-Bilska AT, Reynolds LP, Redmer DA. 2014; Prion (PrPC) expression in ovine uteroplacental tissues increases after estrogen treatment of ovariectomized ewes and during early pregnancy. Reproduction. 148:1-10

32.

Klamt F, Dal-Pizzol F, Conte da Frota ML, Walz R, Andrades ME, da Silva EG, Brentani RR, Izquierdo I, Fonseca Moreira JC. 2001; Imbalance of antioxidant defense in mice lacking cellular prion protein. Free Radic Biol Med. 30:1137-1144

33.

Kovač V, Čurin Šerbec V. 2022; Prion protein: The molecule of many forms and faces. Int J Mol Sci. 23:1232

34.

Li C, Yu S, Nakamura F, Yin S, Xu J, Petrolla AA, Singh N, Tartakoff A, Abbott DW, Xin W, Sy MS. 2009; Binding of pro-prion to filamin a disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer. J Clin Invest. 119:2725-2736

35.

Li QQ, Sun YP, Ruan CP, Xu XY, Ge JH, He J, Xu ZD, Wang Q, Gao WC. 2011; Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival. Cancer Sci. 102:400-406

36.

Liang J, Pan Y, Zhang D, Guo C, Shi Y, Wang J, Chen Y, Wang X, Liu J, Guo X, Chen Z, Qiao T, Fan D. 2007; Cellular prion protein promotes proliferation and G1/S transition of human gastric cancer cells SGC7901 and AGS. FASEB J. 21:2247-2256

37.

Limone A, Maggisano V, Sarnataro D, Bulotta S. 2023; Emerging roles of the cellular prion protein (PrPC) and 37/67 kDa laminin receptor (RPSA) interaction in cancer biology. Cell Mol Life Sci. 80:207

38.

Linden R. 2017; The biological function of the prion protein: A cell surface scaffold of signaling modules. Front Mol Neurosci. 10:77

39.

Liu J, Zhao D, Liu C, Ding T, Yang L, Yin X, Zhou X. 2015; Prion protein participates in the protection of mice from lipopolysaccharide infection by regulating the inflammatory process. J Mol Neurosci. 55:279-287

40.

Makrinou E, Collinge J, Antoniou M. 2002; Genomic characterization of the human prion protein (PrP) gene locus. Mamm Genome. 13:696-703

41.

Málaga-Trillo E, Solis GP, Schrock Y, Geiss C, Luncz L, Thomanetz V, Stuermer CA. 2009; Regulation of embryonic cell adhesion by the prion protein. PLOS Biol. 7:e55

42.

Martellucci S, Santacroce C, Santilli F, Manganelli V, Sorice M, Mattei V. 2020; Prion protein in stem cells: A lipid raft component involved in the cellular differentiation process. Int J Mol Sci. 21:4168

43.

Mattei V, Santacroce C, Tasciotti V, Martellucci S, Santilli F, Manganelli V, Piccoli L, Misasi R, Sorice M, Garofalo T. 2015; Role of lipid rafts in neuronal differentiation of dental pulp-derived stem cells. Exp Cell Res. 339:231-240

44.

Megra BW, Eugenin EA, Berman JW. 2018; Inflammatory mediators reduce surface PrPC on human BMVEC resulting in decreased barrier integrity. Lab Invest. 98:1347-1359

45.

Miranda A, Ramos-Ibeas P, Pericuesta E, Ramirez MA, Gutierrez-Adan A. 2013; The role of prion protein in stem cell regulation. Reproduction. 146:R91-R99

46.

Nandi PK. 1997; Interaction of prion peptide HuPrP106-126 with nucleic acid. Arch Virol. 142:2537-2545

47.

Pantera B, Bini C, Cirri P, Paoli P, Camici G, Manao G, Caselli A. 2009; PrPC activation induces neurite outgrowth and differentiation in PC12 cells: Role for caveolin-1 in the signal transduction pathway. J Neurochem. 110:194-207

48.

Peng HY, Lei ST, Hou SH, Weng LC, Yuan Q, Li MQ, Zhao D. 2022; PrPC promotes endometriosis progression by reprogramming cholesterol metabolism and estrogen biosynthesis of endometrial stromal cells through PPARα pathway. Int J Biol Sci. 18:1755-1772

49.

Pereira RM, Mesquita P, Pires VMR, Baptista MC, Barbas JP, Pimenta J, Horta AEM, Prates JAM, Marques CC. 2018; Prion protein testis specific (PRNT) gene polymorphisms and transcript level in ovine spermatozoa: Implications in freezability, fertilization and embryo production. Theriogenology. 115:124-132

50.

Petit CS, Barreau F, Besnier L, Gandille P, Riveau B, Chateau D, Roy M, Berrebi D, Svrcek M, Cardot P, Rousset M, Clair C, Thenet S. 2012; Requirement of cellular prion protein for intestinal barrier function and mislocalization in patients with inflammatory bowel disease. Gastroenterology. 143:122-132

51.

Prusiner SB. 1991; Molecular biology of prion diseases. Science. 252:1515-1522

52.

Roucou X. 2014; Regulation of PrP(C) signaling and processing by dimerization. Front Cell Dev Biol. 2:57

53.

Sarnataro D, Pepe A, Altamura G, De Simone I, Pesapane A, Nitsch L, Montuori N, Lavecchia A, Zurzolo C. 2016; The 37/67 kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67 kDa LR cell surface localization and interaction with the cellular prion protein. Sci Rep. 6:24457

54.

Schmitz M, Zafar S, Silva CJ, Zerr I. 2014; Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrP(C) for the cytoskeleton. Prion. 8:381-386

55.

Shaked Y, Rosenmann H, Talmor G, Gabizon R. 1999; A C-terminal-truncated PrP isoform is present in mature sperm. J Biol Chem. 274:32153-32158

56.

Sigurdson CJ, Bartz JC, Glatzel M. 2019; Cellular and molecular mechanisms of prion disease. Annu Rev Pathol. 14:497-516

57.

Sorice M, Mattei V, Tasciotti V, Manganelli V, Garofalo T, Misasi R. 2012; Trafficking of PrPC to mitochondrial raft-like microdomains during cell apoptosis. Prion. 6:354-358

58.

Strom A, Diecke S, Hunsmann G, Stuke AW. 2006; Identification of prion protein binding proteins by combined use of far-Western immunoblotting, two dimensional gel electrophoresis and mass spectrometry. Proteomics. 6:26-34

59.

Tanji K, Saeki K, Matsumoto Y, Takeda M, Hirasawa K, Doi K, Matsumoto Y, Onodera T. 1995; Analysis of PrPC mRNA by in situ hybridization in brain, placenta, uterus and testis of rats. Intervirology. 38:309-315

60.

Thumdee P, Ponsuksili S, Murani E, Nganvongpanit K, Gehrig B, Tesfaye D, Gilles M, Hoelker M, Jennen D, Griese J, Schellander K, Wimmers K. 2007; Expression of the prion protein gene (PRNP) and cellular prion protein (PrPC) in cattle and sheep fetuses and maternal tissues during pregnancy. Gene Expr. 13:283-297

61.

Tuo W, Zhuang D, Knowles DP, Cheevers WP, Sy MS, O’Rourke KI. 2001; Prp-c and Prp-Sc at the fetal-maternal interface. J Biol Chem. 276:18229-18234

62.

Vanderperre B, Staskevicius AB, Tremblay G, McCoy M, O’Neill MA, Cashman NR, Roucou X. 2011; An overlapping reading frame in the PRNP gene encodes a novel polypeptide distinct from the prion protein. FASEB J. 25:2373-2386

63.

Walmsley AR, Zeng F, Hooper NM. 2001; Membrane topology influences N-glycosylation of the prion protein. EMBO J. 20:703-712

64.

Walsh KP, Kuhn TB, Bamburg JR. 2014; Cellular prion protein: A co-receptor mediating neuronal cofilin-actin rod formation induced by β-amyloid and proinflammatory cytokines. Prion. 8:375-380