Scroll to top
Prion Protein Mutation Database

PrP Function

The precise physiological function of PrPC is unknown. It is ubiquitously expressed throughout the brain and is enriched at the pre- and post-synaptic membranes, where it is thought to play a critical role in neuronal maintenance and neuroprotection1-2. Additionally, the well-documented ability of PrPC to coordinate Cu2+ and Zn2+ cations 3-4 suggests it plays a role in metal ion homeostasis5. In humans, there are limited data to indicate that heterozygous loss-of-function N-terminal PrPC mutations may not be haploinsufficient, and hence, do not cause an explicit neurologic phenotype6 (see Truncating Mutations); whether homozygous loss of PrPC results in disease is not known2.

The PrPC protein is highly conserved from birds to mammals, indicating strong evolutionary protection, that demands importance in its biological function7. It was therefore, paradoxical to find that PRNP knockout mice displayed no overt phenotype, aside from a resistance to prion infection as concomitant expression of PrPC is required and rate-limiting5,8. Initial Prnp null mouse strains, the first designated Zurich I (ZrchI, PrnpZH1/ZH1) produced in a C57BL/6J x 129/Sv(ev) background9 and a second line of PrPC-deficient mice, known as Edinburgh (Edbg) produced with a pure 129/Ola genetic background10, developed and bred normally, albeit with subtle alterations in behaviour9. Their apparent normality seemed to exclude a physiological PrPC function that is essential for life2. If inactivation of a gene does not lead to an observed abnormal phenotype, there are three possibilities: (1) the abnormal phenotype is present under the conditions currently being used but is yet to be discovered, (2) the abnormal phenotype will only become evidence under environmental conditions that have not yet been tested, or (3) there is no abnormal phenotype11. Indeed, many subsequent studies have revealed that the Prnp knockout mouse has a myriad of phenotypes, some of which have been contested and many of which are subtle2,9,12 – see table.  Furthermore, PrP is one member of the prion protein family, that includes Doppel and Shadoo (see PrP Gene Structure), therefore, paralogous gene redundancy providing functional complementation11 and developmental plasticity12 may also mask the Prnp knockout mouse phenotype. PrPC-deficient mice from which the entire Prnp gene, and not only the open reading frame, was removed13-15 were found to develop progressive cerebellar ataxia, which was originally attributed to the loss of PrPC, but was later discovered to be due to the deletion of a splice acceptor site in exon 3 of Prnp16. This led to aberrant over-expression of the PrPC paralogous gene, Prnd, encoding Doppel16-18, causing selective neurodegeneration of cerebellar Purkinjie cells. Notably, the reintroduction of Prnp in mice over-expressing Prnd in the brain rescued the phenotype, suggesting a functional interaction between PrPC and Doppel in vivo19.

As seen in the table below, disparate functions have been attributed to PrPC on the basis of phenotypes seen in Prnp-deficient mice, yet none have been elucidated mechanistically, and while some studies were consistent among the different PrPC-deficient lines, others yielded contradictory results2,20. A genetic confounder has been shown to account for some of the observed phenotypes2,21. Replication of experiments in strictly co-isogenic mice (Zurich-3, Prnp-deficient mouse on a pure C57BL/6J genetic background)22 have revealed that some phenotypes, such as enhanced macrophage phagocytosis23, are due to polymorphic genes flanking Prnp22, including Sirpa20, which encodes the signal regulatory peptide-α, rather than loss of Prnp itself. Nevertheless, all Prnp-deficient mice are noted to develop a chronic demyelinating polyneuropathy22,24, and PrPC has been shown to promote myelin homeostasis by activating G protein-coupled receptor Gpr126 on Schwann cells25 thusconfirming the importance of PrPC in peripheral myelin maintenance21-22.

Proposed physiological roles of PrPC. Studies of PrP knockout mice published to date are shown. Adapted from Wulf2 and Steele12. Bold indicates mixed genetic background of at least two distinct mouse strains. Italic indicates mice maintained on a single, pure genetic background.

Proposed role of PrPC Phenotype of Prnp0/0 model system Supportive report (mouse model / cell line) Opposing report (mouse model / cell line)
Synaptic transmission and plasticity Reduced long-term potentiation Collinge J 1994 (ZH1) [26]
Manson JC 1995 (Edgb) [27]
Lledo PM 1996 (ZH1, ZH1 back-crossed to FVB) [28]
Laurén J 2009 (ZH1) [29]
Reduced excitatory and inhibitory synaptic transmission Collinge J 1994 (ZH1) [26]
Carleton A 2001 (ZH1, Ngsk) [30]
Lledo PM 1996 (ZH1, ZH1 back-crossed to FVB) [28]
Herms JW 1995 (ZH1) [31]
Memory formation Reduced spatial learning and memory Criado JR 2005 (Edgb [back-]crossed to C57BL/10) [32] Büeler H 1992 (ZH1) [9]
Reduced avoidance learning and memory Coitinho AS 2003 (ZH1) [33]
Nishida N 1997 (Ngsk) [34]
Lipp H-P 1998 (ZH1) [35]
Stabilisation of sleep and circadian rhythm  Altered circadian rhythm, increased sleep fragmentation, increased slow-wave activity after sleep deprivation Tobler I 1996 (ZH1, Edgb) [36] Sánchez-Alavez M 2007 (Edgb [back-]crossed to C57BL/10) [37]
Neuronal excitability  Reduced Kv4.2 currents Mercer RCC 2013 (ZH1, HEK293T) [38]
Reduced slow after hyperpolarisation and calcium-activated potassium currents Herms JW 2000 (ZH1) [39]
Fuhrmann M 2006 (ZH1) [40]
Collinge SB 1996 (ZH1) [41]
Mallucci GR 2002 (Tg35) [42]
Powell AD 2008 (ZH1) [43]
Increased susceptibility to Kainate-induced seizures Carulla P 2011 (ZH1) [44] Striebel JF 2013 (Edbg [back-]crossed to C57BL/10) [45]
Calcium homeostasis Reduced VGCC currents Fuhrmann M 2006 (ZH1) [40] Powell AD 2008 (ZH1) [43]
Increased calcium buffering Powell AD 2008 (ZH1) [43]
Glutamate receptor function Increased NMDA currents, nociception and depressive-like behaviour Khosravani H 2008 (ZH1) [46]
Gadotti VM 2011 and 2012 (ZH1) [4748]
Upregulation of Kainate receptor subunits Carulla P 2011 (ZH1) [44]
Neurite outgrowth Delayed development of cerebellar circuitry Prestori F 2008 (ZH1) [49]
Reduced neurite outgrowth in vitro Beraldo FH 2011 (ZH1) [50]
Toxicity elicited by oligomeric species Protected from reduction of long-term potentiation by toxic Amyloid-β species Laurén J 2009 (ZH1, Edbg backcrossed to C57BL6) [29] Balducci C 2010 (ZH1) [51]
Calella AM 2010 (ZH1) [52]
Kessels HW 2010 (Edgb [back-]crossed to C57BL/10) [53]
Cisse M 2011 (ZH1 backcrossed to FVB) [54]
Neuroprotection Larger lesions in model of acute cerebral ischaemia Weise J 2006 (ZH1) [55]
Doeppner TR 2015 (ZH1) [56]
Mitteregger G 2007 (ZH1) [57]
Descreased SOD1 activity Brown DR 1997 (ZH1) [58] Waggoner DJ 2000 (ZH1) [59]
Copper, zinc, iron and lactate metabolism Reduced zinc content in primary neurons Watt NT 2012 (ZH1, SH-SY5Y) [60]
Increased lactate-uptake in cultured astrocytes Kleene R 2007 (ZH1) [61]
Altered iron and copper metabolism Gasperini L 2016 (ZH1 backcrossed to FVB) [62]
Inflammatory response and phagocytosis Increased macrophage phagocytosis de Almeida 2005 (ZH1) [23] Nuvolone M 2013 (Edbg) [20]
Peripheral myelin maintenance  Bremer J 2010 (ZH1, Edgb) [24]
Nuvolone M 2016 (ZH3) [22]
Küffer A 2016 (ZH1 and ZH3) [25]
Henzi A 2020 (ZH3) [63]


  1. Aguzzi A, Baumann F and Bremer J. The Prion’s Elusive Reason for Being. Annual Review of Neuroscience 2008; 31: 439-477. (PMID: 18558863)
  2. Wulf M-A, Senatore A and Aguzzi A. The biological function of the cellular prion protein: an update. BMC Biology 2017; 15: 34. (PMID: 28464931)
  3. Markham KA, Roseman GP, Linsley RB et al. Molecular Features of the Zn2+ Binding Site in the Prion Protein Probed by 113Cd NMR. Biophysical Journal 2019; 116(4): 610-620. (PMID: 30678993)
  4. Evans EGB, Pushie, MJ, Markham KA et al. Interaction between the Prion Protein’s Copper-Bound Octarepeat Domain and a Charged C-terminal Pocket Suggests a Mechanism for N-terminal Regulation. Structure 2016; 24(7): 1057-1067. (PMID: 27265848)
  5. Bernardi L and Bruni AC. Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review. International Journal of Molecular Sciences 2019; 20(14): 3606. (PMID: 31340582)
  6. Minikel EV, Vallabh SM, Lek M et al. Quantifying prion disease penetrance using large population control cohorts. Science Translational Medicine 2016; 8(322): 322ra9. (PMID: 26791950)
  7. Wopfner F, Weidenhöfer G, Schneider R et al. Analysis of 27 mammalian and 9 avian PrPs reveals high conservation of flexible regions of the prion protein. Journal of Molecular Biology 1999; 289(5): 1163-1178. (PMID: 10373359)
  8. Büeler H, Aguzzi A, Sailer A et al. Mice devoid of PrP are resistant to scrapie. Cell 1993; 73(7): 1339-1347. (PMID: 8100741)
  9. Büeler H, Fischer M, Lang Y et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992; 356(6370): 577-582. (PMID: 1373228)
  10. Manson JC, Clarke AR, Hooper ML et al. 129/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal. Molecular Neurobiology 1994; 8(2-3): 121-127. (PMID: 7999308)
  11. Barbaric I, Miller G, Dear NT. Appearances can be deceiving: phenotypes of knockout mice. Briefings in Functional Genomics 2007; 6(2): 91-103. (PMID: 17584761)
  12. Steele AD, Lindquist S, Aguzzi A. The Prion Protein Knockout Mouse. Prion 2007; 1(2): 83-93. (PMID: 19164918)
  13. Sakaguchi S, Katamine S, Nishida N et al. Loss of cerebellar Purkinje cells in aged mice homozygous for a disrupted PrP gene. Nature 1996; 380(6574): 528-531. (PMID: 8606772) 
  14. Katamine S, Nishida N, Sugimoto T et al. Impaired motor coordination in mice lacking prion protein. Cellular and molecular Neurobiology 1998; 18(6): 731-742. (PMID: 9876879)
  15. Rossi D, Cozzio A, Flechsig et al. Onset of ataxia and Purkinje cell loss in PrP null mice inversely correlated with Dpl level in brain. The EMBO Journal 2001; 20(4): 694-702. (PMID: 11179214)
  16. Weissmann C and Aguzzi A. PrP’s Double Causes Trouble. Science 1999; 286(5441): 914-915. (PMID: 10577243)
  17. Moore RC, Lee IY, Silverman et al. Ataxia in prion protein (PrP)-deficient mice is associated with upregulation of the novel PrP-like protein doppel. Journal of Molecular Biology 1999; 292(4): 797-817. (PMID: 10525406)
  18. Lu K, Wang W, Xie Z et al. Expression and Structural Characterisation of the Recombinant Human Doppel Protein. Biochemistry 2000; 39(44): 13575-13583. (PMID: 11063595)
  19. Moore RC, Mastrangelo P, Bouzamondo E et al. Doppel-induced cerebellar degeneration in transgenic mice. Proceedings of the National Academy of Sciences 2001; 98(26): 15288-15293. (PMID: 11734625)
  20. Nuvolone M, Kana V, Hutter G et al. SIRPα polymorphisms. But not the prion protein, control phagocytosis of apoptotic cells. Journal of Experimental Medicine 2013; 210(12): 2539-2552. (PMID: 24145514)
  21. Scheckel C and Aguzzi A. Prions, prionoids and protein misfolding disorders. Nature Review Genetics 2018; 19: 405-418. (PMID: 29713012)
  22. Nuvolone M, Hermann M, Source S et al. Strictly co-isogenic C57BL/6J-Prnp-/- mice: A rigorous resource for prion science. Journal of Experimental Medicine 2016; 213(3): 313-327. (PMID: 26926995)
  23. de Almeida CJG, Chiarini LB, da Silva JP et al. The cellular prion protein modulates phagocytosis and inflammatory response. Journal of Leukocyte Biology 2005; 77(2): 238-246. (PMID: 15539455)
  24. Bremer J, Baumann F, Tiberi C et al. Axonal prion protein is required for peripheral myelin maintenance. Nature Neuroscience 2010; 13(3): 310-318. (PMID: 20098419)
  25. Küffer A, Lakkaraju AK, Mogha A et al. The prion protein is an antagonistic ligand of the G protein-coupled receptor Adgrg6. Nature 2016; 536(7617): 464-468. (PMID: 27501152)
  26. Collinge J, Whittington MA, Sidle KCL et al. Prion protein is necessary for normal synaptic function. Nature 1994; 370(6487): 295-297. (PMID: 8035877) 
  27. Manson JC, Hope J, Clarke AR et al. PrP gene dosage and long term potentiation. Neurodegeneration 1995; 4(1): 113-114. (PMID: 7600180)
  28. Lledo PM, Tremblay P, DeArmond SJ et al. Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus. Proceedings of the National Academy of Sciences 1996; 93(6): 2403-2407. (PMID: 8637886)
  29. Laurén J, Gimbel DA, Nygaard HB et al. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 2009; 457(7233): 1128-1132. (PMID: 19242475)
  30. Carleton A, Tremblay P, Vincent J-D, Lledo PM. Dose-dependent prion protein (PrP)-mediated facilitation of excitatory synaptic transmission in the mouse hippocampus. Pflugers Archiv European Journal of Physiology 2001; 442(2): 223-229. (PMID: 11417218)
  31. Herms JW, Kretzschmar HA, Titz S, Keller BU. Patch-clamp Analysis of Synpatic Transmission to Cerebellar Purkinjie Cells of Prion Protein Knockout Mice. European Journal of Neuroscience 1995; 7(12): 2508-2512. (PMID: 8845956)
  32. Criado JR, Sanchez-Alavez M, Conti B et al. Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons. Neurobiology of Disease 2005; 19(1-2): 225-265. (PMID: 15837581)
  33. Coitinho AS, Roesler R, Martins VR et al. Cellular prion protein ablation impairs behaviour as a function of age. Neuroreport 2003; 14(10): 1375-1379. (PMID: 12876477)
  34. Nishida N, Katamine S, Shigematsu K et al. Prion protein is necessary for latent learning and long-term memory retention. Cellular and Molecular Neurobiology 1997; 17(5): 537-545. (PMID: 9353594)
  35. Lipp H-P, Stagliar-Bozicevic M, Fischer M, Wolfer DP. A 2-year longitudinal study of swimming navigation in mice devoid of the prion protein: no evidence for neurological anomalies or spatial learning impairments. Behavioural Brain Research 1998; 95(1): 47-54. (PMID: 9754876)
  36. Tobler I, Gaus SE, Deboer T et al. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature 1996; 380(6575): 639-642. (PMID: 8602267)
  37. Sánchez-Alavez M, Conti B, Moroncini G, Criado JR. Contributions of neuronal prion protein on sleep recovery and stress response following sleep deprivation. Brain Research 2007; 1158: 71-80. (PMID: 17570349)
  38. Mercer RC, Ma L, Watts JC et al. The prion Protein Modulates A-type K+ Currents Mediated by Kv4.2 Complexes through Dipeptidyl Aminopeptidases-like Protein 6. Journal of Biological Chemistry 2013; 288(52): 37241-37255. (PMID: 24225951)
  39. Herms JW, Korte S, Gall S et al. Altered intracellular calcium homeostasis in cerebellar granule cells of prion protein-deficient mice. Journal of Neurochemistry 2000; 75(4): 1487-1492. (PMID: 10987828)
  40. Fuhrmann M, Bittner T, Mitteregger G et al. Loss of the cellular prion protein affects the Ca2+ homeostasis in hippocampal CA1 neurons. Journal of Neurochemistry 2006; 98(6): 1876-1885. (PMID: 16945105)
  41. Collinge SB, Collinge J and Jefferys JGR. Hippocampal slices from prion protein null mice: disrupted Ca2+-activated K+ currents. Neuroscience Letters 1996; 209(1): 49-52. (PMID: 8734907)
  42. Mallucci GR, Ratté S, Asante EA et al. Post-natal knockout of prion protein alters hippocampal CAI properties, but does not result in neurodegeneration. EMBO Journal 2002; 21(3): 202-210. (PMID: 11823413)
  43. Powell AD, Toescu EC, Collinge J, Jefferys JGR. Alterations in Ca2+-Buffering in Prion-Null Mice: Association with Reduced Afterhyperpolarisations in CA1 Hippocampal Neurons. Journal fo Neuroscience 2008; 28(15): 3877-3886. (PMID: 18400886)
  44. Carulla P, Bribián A, Rangel A et al. Neuroprotective role f PrPC against Kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding. Molecular Biology of the Cell 2011; 22(17): 3041-3054. (PMID: 21757544) 
  45. Striebel JF, Race B, Pathmajeyan M et al. Lack of influence of prion protein gene expression on kainite-induced seizures in mice: studies using congenic, coisogenic and transgenic strains. Neuroscience 2013; 238: 11-18. (PMID: 23415788)
  46. Khosravani H, Zhang Y, Tsutsui S et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. Journal of Cell Biology 2008; 181(3): 551-565. (PMID: 18443219)
  47. Gadotti VM and Zamponi GW. Cellular Prion Protein Protects from inflammatory and Neuropathic Pain. Molecular Pain 2011; 7: 59. (PMID: 21843375)
  48. Gadotti VM, Bonfield SP and Zamponi GW. Depressive-like behaviour of mice lacking cellular prion protein. Behavioural Brain Research 2012; 227(2): 319-232. (PMID: 21439331)
  49. Prestori F, Rossi P, Bearzatto B et al. Altered Neuron Excitability and Synaptic Plasticity in the Cerebellar Granular Layer of Juvenile Prion Protein Knock-Out Mice with Impaired Motor Control. Journal of Neuroscience 2008; 28(28): 7091-7103. (PMID: 18614678)
  50. Beraldo FH, Arantes CP, Santos TG et al. Metabotropic glutamate receptors transduce signals for neurite outgrowth after binding of the prion protein to laminin γ1 chain. FASEB Journal 2011; 25(1): 265-279. (PMID: 20876210)
  51. Balducci C, Beeg M, Stravalaci M et al. Synthetic amyloid-β oligomers impair long-term memory independent of cellular prion protein. Proceedings of the National Academy of Sciences 2010; 107(5): 2295-2300. (PMID: 20133875)
  52. Calella AM, Farinelli M, Nuvolone M et al. Prion protein and Aβ-related synaptic toxicity impairment. EMBO Molecular Medicine 2010; 2(8): 306-314. (PMID: 20665634)
  53. Kessels HW, Nguyen LN, Nabavi S, Malinow R. The prion protein as a receptor for amyloid-β. Nature 2010; 466(7308): E3-E4. (PMID: 20703260)
  54. Cisse M, Sanchez PE, Kim DH et al. Ablation of Cellular Prion Protein Does Not Ameliorate Abnormal Neural network Activity or Cognitive Dysfunction in the J20 Line of Human Amyloid Precursor Transgenic Mice. Journal of Neuroscience 2011; 31(29): 10427-10431. (PMID: 21775587)
  55. Weise J, Sandau R, Schwarting S et al. Deletion of cellular prion protein results in reduced Akt activation, enhanced postischaemic caspase-3 activation, and exacerbation of ischaemic brain injury. Stroke 2006; 37(5): 1296-1300. (PMID: 16574930)
  56. Doeppner TR, Kaltwasser B, Schlechter J et al. Cellular prion protein promotes post-ischaemic neuronal survival, angioneurogenesis and enhances neural progenitor cell homing via proteasome inhibition. Cell Death and Disease 2015; 6(12): e2024. (PMID: 26673668)
  57. Mitteregger G, Vosko M, Krebs B et al. The role of octarepeat region in neuroprotective function of the cellular prion protein. Brain Pathology 2007; 17(2): 174-183. (PMID: 17388948)
  58. Brown DR, Schulz-Schaeffer WJ, Schmidt B, Kretzachmar HA. Prion Protein-Deficient Cells Show Altered Response to Oxidative Stress Due to Decreased SOD-1 Activity. Experimental Neurology 1997; 146(1): 104-112. (PMID: 9225743)
  59. Waggoner DJ, Drisaldi B, Bartnikas TB et al. Brain Copper Content and Cuproenzyme Activity Do Not Vary with Prion Protein Expression Level. Journal of Biological Chemistry 2000; 275(11): 7455-7458. (PMID: 10713045)
  60. Watt NT, Taylor DR, Kerrigan TL et al. Prion protein facilitates uptake of zinc into neuronal cells. Nature Communications 2012; 3: 1134. (PMID: 23072804)
  61. Kleene R, Loers G, Langer J et al. Prion Protein Regulates Glutamate-Dependent Lactate Transport of Astrocytes. Journal of Neuroscience 2007; 27(45): 12331-12340. (PMID: 17989297)
  62. Gasperini L, Meneghetti E, Legname G, Benetti F. In Absence of the Cellular Prion Protein, Alterations in Copper Metabolism and Copper-Dependent Oxidase Activity Affect Iron Distribution. Frontiers in Neuroscience 2016; 10: 437. (PMID: 27729845)
  63. Henzi A, Senatore A, Lakkaraju AK et al. Soluble dimeric prion protein ligand activates Adgrg6 receptor but does not rescue early signs of demyelination in PrP-deficient mice. PLOS One 2020; 15(11): e0242137. (PMID: 33180885)