Normal cellular prion protein (PrPC) is a conserved mammalian glycoprotein found on the outer plasma membrane leaflet through a glycophosphatidylinositol anchor. Although PrPC is expressed by a wide range of tissues throughout the body, the complete repertoire of its functions has not been fully determined. The misfolded pathogenic isoform PrPSc (the scrapie form of PrP) is a causative agent of neurodegenerative prion diseases. The aim of this study is to evaluate PrPC localisation, expression and trafficking in pancreases from organ donors with and without type 1 diabetes and to infer PrPC function through studies on interacting protein partners.
In order to evaluate localisation and trafficking of PrPC in the human pancreas, 12 non-diabetic, 12 type 1 diabetic and 12 autoantibody-positive organ donor tissue samples were analysed using immunofluorescence analysis. Furthermore, total RNA was isolated from 29 non-diabetic, 29 type 1 diabetic and 24 autoantibody-positive donors to estimate PrPC expression in the human pancreas. Additionally, we performed PrPC-specific immunoblot analysis on total pancreatic protein from non-diabetic and type 1 diabetic organ donors to test whether changes in PrPC mRNA levels leads to a concomitant increase in PrPC protein levels in human pancreases.
In non-diabetic and type 1 diabetic pancreases (the latter displaying both insulin-positive [INS(+)] and -negative [INS(−)] islets), we found PrPC in islets co-registering with beta cells in all INS(+) islets and, strikingly, unexpected activation of PrPC in alpha cells within diabetic INS(−) islets. We found PrPC localised to the plasma membrane and endoplasmic reticulum (ER) but not the Golgi, defining two cellular pools and an unconventional protein trafficking mechanism bypassing the Golgi. We demonstrate PrPC co-registration with established protein partners, neural cell adhesion molecule 1 (NCAM1) and stress-inducible phosphoprotein 1 (STI1; encoded by STIP1) on the plasma membrane and ER, respectively, linking PrPC function with cyto-protection, signalling, differentiation and morphogenesis. We demonstrate that both PRNP (encoding PrPC) and STIP1 gene expression are dramatically altered in type 1 diabetic and autoantibody-positive pancreases.
As the first study to address PrPC expression in non-diabetic and type 1 diabetic human pancreas, we provide new insights for PrPC in the pathogenesis of type 1 diabetes. We evaluated the cell-type specific expression of PrPC in the human pancreas and discovered possible connections with potential interacting proteins that we speculate might address mechanisms relevant to the role of PrPC in the human pancreas.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Application for datasets generated during and/or analysed during the current study may be considered by the corresponding author on reasonable request.
Minimum Information for Publication of Quantitative Real-Time PCR Experiments
Neural cell adhesion molecule 1
- PrPC :
Cellular prion protein
- PrPSc :
Scrapie form of prion protein (pathogenic, alternatively folded aggregate)
Stress-inducible phosphoprotein 1
United Network for Organ Sharing
Wolfram syndrome 1
Prusiner SB (1998) The prion diseases. Brain Pathol 8(3):499–513
Wulf MA, Senatore A, Aguzzi A (2017) The biological function of the cellular prion protein: an update. BMC Biol 15(1):34. https://doi.org/10.1186/s12915-017-0375-5
Atkinson CJ, Zhang K, Munn AL, Wiegmans A, Wei MQ (2016) Prion protein scrapie and the normal cellular prion protein. Prion 10(1):63–82. https://doi.org/10.1080/19336896.2015.1110293
Kovacs GG, Budka H (2008) Prion diseases: from protein to cell pathology. Am J Pathol 172(3):555–565. https://doi.org/10.2353/ajpath.2008.070442
Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216(4542):136–144. https://doi.org/10.1126/science.6801762
Otero A, Duque Velasquez C, Johnson C et al (2019) Prion protein polymorphisms associated with reduced CWD susceptibility limit peripheral PrP(CWD) deposition in orally infected white-tailed deer. BMC Vet Res 15(1):50. https://doi.org/10.1186/s12917-019-1794-z
Ryskalin L, Busceti CL, Biagioni F et al (2019) Prion protein in glioblastoma multiforme. Int J Mol Sci 20(20). https://doi.org/10.3390/ijms20205107
Castle AR, Gill AC (2017) Physiological functions of the cellular prion protein. Front Mol Biosci 4:19. https://doi.org/10.3389/fmolb.2017.00019
Tee BL, Longoria Ibarrola EM, Geschwind MD (2018) Prion diseases. Neurol Clin 36(4):865–897. https://doi.org/10.1016/j.ncl.2018.07.005
Asher DM, Gregori L (2018) Human transmissible spongiform encephalopathies: historic view. Handb Clin Neurol 153:1–17. https://doi.org/10.1016/B978-0-444-63945-5.00001-5
Kovacs GG, Budka H (2009) Molecular pathology of human prion diseases. Int J Mol Sci 10(3):976–999. https://doi.org/10.3390/ijms10030976
Corbett GT, Wang Z, Hong W et al (2020) PrP is a central player in toxicity mediated by soluble aggregates of neurodegeneration-causing proteins. Acta Neuropathol 139(3):503–526. https://doi.org/10.1007/s00401-019-02114-9
Westergard L, Christensen HM, Harris DA (2007) The cellular prion protein (PrP(C)): its physiological function and role in disease. Biochim Biophys Acta 1772(6):629–644. https://doi.org/10.1016/j.bbadis.2007.02.011
Atouf F, Scharfmann R, Lasmezas C, Czernichow P (1994) Tight hormonal control of PrP gene expression in endocrine pancreatic cells. Biochem Biophys Res Commun 201(3):1220–1226. https://doi.org/10.1006/bbrc.1994.1835
Ashok A, Singh N (2018) Prion protein modulates glucose homeostasis by altering intracellular iron. Sci Rep 8(1):6556. https://doi.org/10.1038/s41598-018-24786-1
Strom A, Wang GS, Reimer R, Finegood DT, Scott FW (2007) Pronounced cytosolic aggregation of cellular prion protein in pancreatic beta-cells in response to hyperglycemia. Lab Investig 87(2):139–149. https://doi.org/10.1038/labinvest.3700500
Strom A, Wang GS, Scott FW (2011) Impaired glucose tolerance in mice lacking cellular prion protein. Pancreas 40(2):229–232. https://doi.org/10.1097/mpa.0b013e3181f7e547
Amselgruber WM, Buttner M, Schlegel T, Schweiger M, Pfaff E (2006) The normal cellular prion protein (PrPc) is strongly expressed in bovine endocrine pancreas. Histochem Cell Biol 125(4):441–448. https://doi.org/10.1007/s00418-005-0089-6
de Brito G, Lupinacci FC, Beraldo FH et al (2017) Loss of prion protein is associated with the development of insulin resistance and obesity. Biochem J 474(17):2981–2991. https://doi.org/10.1042/BCJ20170137
Zhu C, Schwarz P, Abakumova I, Aguzzi A (2015) Unaltered prion pathogenesis in a mouse model of high-fat diet-induced insulin resistance. PLoS One 10(12):e0144983. https://doi.org/10.1371/journal.pone.0144983
Eberhard D (2013) Neuron and beta-cell evolution: learning about neurons is learning about beta-cells. Bioessays 35(7):584. https://doi.org/10.1002/bies.201300035
Visner GA, Dougall WC, Wilson JM, Burr IA, Nick HS (1990) Regulation of manganese superoxide dismutase by lipopolysaccharide, interleukin-1, and tumor necrosis factor. Role in the acute inflammatory response. J Biol Chem 265(5):2856–2864. https://doi.org/10.1016/S0021-9258(19)39880-1
Bustin SA, Benes V, Garson JA et al (2009) The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin Chem 55(4):611–622. https://doi.org/10.1373/clinchem.2008.112797
Torres M, Cartier L, Matamala JM, Hernandez N, Woehlbier U, Hetz C (2012) Altered prion protein expression pattern in CSF as a biomarker for Creutzfeldt-Jakob disease. PLoS One 7(4):e36159. https://doi.org/10.1371/journal.pone.0036159
Lewis V, Hooper NM (2011) The role of lipid rafts in prion protein biology. Front Biosci (Landmark Ed) 16:151–168. https://doi.org/10.2741/3681
Takeda K, Inoue H, Tanizawa Y et al (2001) WFS1 (Wolfram syndrome 1) gene product: predominant subcellular localization to endoplasmic reticulum in cultured cells and neuronal expression in rat brain. Hum Mol Genet 10(5):477–484. https://doi.org/10.1093/hmg/10.5.477
Puthenveedu MA, Bachert C, Puri S, Lanni F, Linstedt AD (2006) GM130 and GRASP65-dependent lateral cisternal fusion allows uniform Golgi-enzyme distribution. Nat Cell Biol 8(3):238–248. https://doi.org/10.1038/ncb1366
Dworzak MN, Fritsch G, Buchinger P et al (1994) Flow cytometric assessment of human MIC2 expression in bone marrow, thymus, and peripheral blood. Blood 83(2):415–425. https://doi.org/10.1182/blood.V83.2.415.415
Grieve AG, Rabouille C (2011) Golgi bypass: skirting around the heart of classical secretion. Cold Spring Harb Perspect Biol 3(4):a005298. https://doi.org/10.1101/cshperspect.a005298
Gee HY, Noh SH, Tang BL, Kim KH, Lee MG (2011) Rescue of DeltaF508-CFTR trafficking via a GRASP-dependent unconventional secretion pathway. Cell 146(5):746–760. https://doi.org/10.1016/j.cell.2011.07.021
Beery ML, Jacobsen LM, Atkinson MA, Butler AE, Campbell-Thompson M (2019) Islet amyloidosis in a child with type 1 diabetes. Islets 11(2):44–49. https://doi.org/10.1080/19382014.2019.1599707
Couce M, O'Brien TD, Moran A, Roche PC, Butler PC (1996) Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis. J Clin Endocrinol Metab 81(3):1267–1272. https://doi.org/10.1210/jcem.81.3.8772610
Maloy AL, Longnecker DS, Greenberg ER (1981) The relation of islet amyloid to the clinical type of diabetes. Hum Pathol 12(10):917–922. https://doi.org/10.1016/s0046-8177(81)80197-9
Mukherjee A, Morales-Scheihing D, Butler PC, Soto C (2015) Type 2 diabetes as a protein misfolding disease. Trends Mol Med 21(7):439–449. https://doi.org/10.1016/j.molmed.2015.04.005
Mukherjee A, Soto C (2017) Prion-like protein aggregates and type 2 diabetes. Cold Spring Harb Perspect Med 7(5):a024315. https://doi.org/10.1101/cshperspect.a024315
Gupta D, Leahy JL (2014) Islet amyloid and type 2 diabetes: overproduction or inadequate clearance and detoxification? J Clin Invest 124(8):3292–3294. https://doi.org/10.1172/JCI77506
Yakupova EI, Bobyleva LG, Vikhlyantsev IM, Bobylev AG (2019) Congo Red and amyloids: history and relationship. Biosci Rep 39(1):BSR20181415. https://doi.org/10.1042/BSR20181415
Xue C, Lin TY, Chang D, Guo Z (2017) Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. R Soc Open Sci 4(1):160696. https://doi.org/10.1098/rsos.160696
da Fonseca ACC, Matias D, Geraldo LHM et al (2020) The multiple functions of the co-chaperone stress inducible protein 1. Cytokine Growth Factor Rev. https://doi.org/10.1016/j.cytogfr.2020.06.003
Schmitt-Ulms G, Legname G, Baldwin MA et al (2001) Binding of neural cell adhesion molecules (N-CAMs) to the cellular prion protein. J Mol Biol 314(5):1209–1225. https://doi.org/10.1006/jmbi.2000.5183
Hernandez MP, Sullivan WP, Toft DO (2002) The assembly and intermolecular properties of the hsp70-Hop-hsp90 molecular chaperone complex. J Biol Chem 277(41):38294–38304. https://doi.org/10.1074/jbc.M206566200
Sytnyk V, Leshchyns'ka I, Schachner M (2017) Neural cell adhesion molecules of the immunoglobulin superfamily regulate synapse formation, maintenance, and function. Trends Neurosci 40(5):295–308. https://doi.org/10.1016/j.tins.2017.03.003
Zanata SM, Lopes MH, Mercadante AF et al (2002) Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J 21(13):3307–3316. https://doi.org/10.1093/emboj/cdf325
Lopes MH, Hajj GN, Muras AG et al (2005) Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J Neurosci 25(49):11330–11339. https://doi.org/10.1523/JNEUROSCI.2313-05.2005
Mehrabian M, Brethour D, Wang H, Xi Z, Rogaeva E, Schmitt-Ulms G (2015) The prion protein controls polysialylation of neural cell adhesion molecule 1 during cellular morphogenesis. PLoS One 10(8):e0133741. https://doi.org/10.1371/journal.pone.0133741
Chakravarthy H, Gu X, Enge M et al (2017) Converting adult pancreatic islet alpha cells into beta cells by targeting both Dnmt1 and Arx. Cell Metab 25(3):622–634. https://doi.org/10.1016/j.cmet.2017.01.009
Miranda A, Ramos-Ibeas P, Pericuesta E, Ramirez MA, Gutierrez-Adan A (2013) The role of prion protein in stem cell regulation. Reproduction 146(3):R91–R99. https://doi.org/10.1530/REP-13-0100
Steele AD, Emsley JG, Ozdinler PH, Lindquist S, Macklis JD (2006) Prion protein (PrPc) positively regulates neural precursor proliferation during developmental and adult mammalian neurogenesis. Proc Natl Acad Sci U S A 103(9):3416–3421. https://doi.org/10.1073/pnas.0511290103
Viotti C (2016) ER to Golgi-dependent protein secretion: the conventional pathway. Methods Mol Biol 1459:3–29. https://doi.org/10.1007/978-1-4939-3804-9_1
Maeda Y, Kinoshita T (2011) Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins. Prog Lipid Res 50(4):411–424. https://doi.org/10.1016/j.plipres.2011.05.002
Rabouille C (2017) Pathways of unconventional protein secretion. Trends Cell Biol 27(3):230–240. https://doi.org/10.1016/j.tcb.2016.11.007
Ostapchenko VG, Beraldo FH, Mohammad AH et al (2013) The prion protein ligand, stress-inducible phosphoprotein 1, regulates amyloid-beta oligomer toxicity. J Neurosci 33(42):16552–16564. https://doi.org/10.1523/JNEUROSCI.3214-13.2013
Beraldo FH, Ostapchenko VG, Xu JZ et al (2018) Mechanisms of neuroprotection against ischemic insult by stress-inducible phosphoprotein-1/prion protein complex. J Neurochem 145(1):68–79. https://doi.org/10.1111/jnc.14281
Roucou X, Giannopoulos PN, Zhang Y, Jodoin J, Goodyer CG, LeBlanc A (2005) Cellular prion protein inhibits proapoptotic Bax conformational change in human neurons and in breast carcinoma MCF-7 cells. Cell Death Differ 12(7):783–795. https://doi.org/10.1038/sj.cdd.4401629
Gill AC, Castle AR (2018) The cellular and pathologic prion protein. Handb Clin Neurol 153:21–44. https://doi.org/10.1016/B978-0-444-63945-5.00002-7
White SA, Zhang LS, Pasula DJ, Yang YHC, Luciani DS (2020) Bax and Bak jointly control survival and dampen the early unfolded protein response in pancreatic beta-cells under glucolipotoxic stress. Sci Rep 10(1):10986. https://doi.org/10.1038/s41598-020-67755-3
Santuccione A, Sytnyk V, Leshchyns’ka I, Schachner M (2005) Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J Cell Biol 169(2):341–354. https://doi.org/10.1083/jcb.200409127
Mehrabian M, Hildebrandt H, Schmitt-Ulms G (2016) NCAM1 polysialylation: the prion protein’s elusive reason for being? ASN Neuro 8(6):1759091416679074. https://doi.org/10.1177/1759091416679074
Linden R (2017) The biological function of the prion protein: a cell surface scaffold of signaling modules. Front Mol Neurosci 10:77. https://doi.org/10.3389/fnmol.2017.00077
The authors would like to thank the organ donors and their families for their precious contributions to nPOD for research, without which this work would not be possible. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org//for-partners/npod-partners/.
Authors’ relationships and activities
The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.
Research reported in this publication was supported by the network for Pancreatic Organ donors with Diabetes (nPOD; RRID-SCR_014541), a collaborative type 1 diabetes research project sponsored by JDRF (nPOD:5-SRA-2018-557-Q-R) and The Leona M. & Harry B. Helmsley Charitable Trust (grant no. 2018PG-T1D053), as well as NIH grant 1UC4DK108132-01, principal investigator MAA. In addition, the Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org//for-partners/npod-partners/.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Hiller, H., Yang, C., Beachy, D.E. et al. Altered cellular localisation and expression, together with unconventional protein trafficking, of prion protein, PrPC, in type 1 diabetes. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05501-8
- Cellular prion protein
- Protein trafficking
- Stress-induced phosphoprotein 1
- Type 1 diabetes
- Type 1 diabetes-dependent endocrine cell expression