Major prion protein: Difference between revisions

The '''Majormajor prion protein''' ('''(PrP)''') is encoded in the human body by the ''PRNP'' [[gene]] also known as '''CD230''' ([[cluster of differentiation]] 230).<ref name = "pmid3755672">{{cite journal | vauthors = Kretzschmar HA, Stowring LE, Westaway D, Stubblebine WH, Prusiner SB, Dearmond SJ | title = Molecular cloning of a human prion protein cDNA | journal = DNA | volume = 5 | issue = 4 | pages = 315–24315–324 | date = August 1986 | pmid = 3755672 | doi = 10.1089/dna.1986.5.315 }}</ref><ref name = "pmid3094007">{{cite journal | vauthors = Sparkes RS, Simon M, Cohn VH, Fournier RE, Lem J, Klisak I, Heinzmann C, Blatt C, Lucero M, Mohandas T | display-authors = 6 | title = Assignment of the human and mouse prion protein genes to homologous chromosomes | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 83 | issue = 19 | pages = 7358–627358–7362 | date = October 1986 | pmid = 3094007 | pmc = 386716 | doi = 10.1073/pnas.83.19.7358 | doi-access = free | bibcode = 1986PNAS...83.7358S | doi-access = free }}</ref><ref name = "pmid3014653">{{cite journal | vauthors = Liao YC, Lebo RV, Clawson GA, Smuckler EA | title = Human prion protein cDNA: molecular cloning, chromosomal mapping, and biological implications | journal = Science | volume = 233 | issue = 4761 | pages = 364–7364–367 | date = July 1986 | pmid = 3014653 | doi = 10.1126/science.3014653 | bibcode = 1986Sci...233..364L }}</ref><ref name = "pmid2877664">{{cite journal | vauthors = Robakis NK, Devine-Gage EA, Jenkins EC, Kascsak RJ, Brown WT, Krawczun MS, Silverman WP | title = Localization of a human gene homologous to the PrP gene on the p arm of chromosome 20 and detection of PrP-related antigens in normal human brain | journal = Biochem.Biochemical Biophys.and Res.Biophysical Commun.Research Communications | volume = 140 | issue = 2 | pages = 758–65758–765 | date = October 1986 | pmid = 2877664 | doi = 10.1016/0006-291X(86)90796-5 }}</ref> Expression of the [[protein]] is most predominant in the [[nervous system]] but occurs in many other tissues throughout the body.<ref name = "pmid11357156">{{cite journal | vauthors = Prusiner SB | title = Shattuck lecture--neurodegenerative diseases and prions | journal = NThe EnglNew JEngland Journal of MedMedicine | volume = 344 | issue = 20 | pages = 1516–261516–1526 | yeardate = May 2001 | pmid = 11357156 | doi = 10.1056/NEJM200105173442006 | doi-access = free }}</ref><ref name = "pmid15494743">{{cite journal | vauthors = Weissmann C | title = The state of the prion | journal = NatNature RevReviews. MicrobiolMicrobiology | volume = 2 | issue = 11 | pages = 861–71861–871 | yeardate = November 2004 | pmid = 15494743 | doi = 10.1038/nrmicro1025 | s2cid = 20992257 }}</ref><ref name = "review2">{{cite journal | vauthors = Zomosa-Signoret V, Arnaud JD, Fontes P, Alvarez-Martinez MT, Liautard JP | title = Physiological role of the cellular prion protein | journal = Vet.Veterinary Res.Research | volume = 39 | issue = 4 | pages = 9 | year = 2008 | pmid = 18073096 | doi = 10.1051/vetres:2007048| url = https://hal.archives-ouvertes.fr/hal-00902908/file/hal-00902908.pdf | doi-access = free }}</ref>

The protein can exist in multiple [[isoforms]]: the normal '''PrP^C''' form, and the [[protease]]-resistant form designated '''PrP^Res''' such as the disease-causing '''PrP^Sc(scrapie)''' (scrapie) and an isoform located in [[mitochondria]]. The [[Protein folding#Protein misfolding and neurodegenerative disease|misfolded]] version PrP^Sc is associated with a variety of [[cognitive disorder]]s and [[Neurodegeneration|neurodegenerative]] diseases such as in animals: [[ovine]] [[scrapie]], [[bovine spongiform encephalopathy]] (BSE, mad cow disease), [[feline spongiform encephalopathy]], [[transmissible mink encephalopathy]] (TME), [[exotic ungulate encephalopathy]], [[chronic wasting disease]] (CWD) which affects [[deer]]; and in humans: [[Creutzfeldt–Jakob disease]] (CJD), [[fatal familial insomnia]] (FFI), [[Gerstmann–Sträussler–Scheinker syndrome]] (GSS), [[Kuru (disease)|kuru]], and [[variant Creutzfeldt–Jakob disease]] (vCJD). Similarities exist between kuru, thought to be due to human ingestion of diseased individuals, and vCJD, thought to be due to human ingestion of BSE-tainted cattle products.

PrP is highly conserved through mammals, lending credence to application of conclusions from test animals such as mice.<ref name = "pmid21987789">{{cite journal | vauthors = Damberger FF, Christen B, Pérez DR, Hornemann S, Wüthrich K | title = Cellular prion protein conformation and function | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 108 | issue = 42 | pages = 17308–1317308–17313 | date = October 2011 | pmid = 21987789 | pmc = 3198368 | doi = 10.1073/pnas.1106325108 | bibcodedoi-access = 2011PNAS..10817308Dfree | doi-accessbibcode = free2011PNAS..10817308D }}</ref> Comparison between primates is especially similar, ranging from 92.9- to 99.6% similarity in [[Peptide sequence|amino acid sequences]]. The human protein structure consists of a globular domain with three [[Alpha helix|α-helices]] and a two-strand [[Antiparallel (biochemistry)|antiparallel]] [[Beta sheet|β-sheet]], an [[amineNH2-terminal|NH₂]]-terminal]] tail, and a short [[Carboxylic acid|COOH]]-terminal tail.<ref name = "pmid7837269">{{cite journal | vauthors = Schätzl HM, Da Costa M, Taylor L, Cohen FE, Prusiner SB | title = Prion protein gene variation among primates | journal = J.Journal Mol.of Biol.Molecular Biology | volume = 245 | issue = 4 | pages = 362–74362–374 | date = January 1995 | pmid = 7837269 | doi = 10.1006/jmbi.1994.0030 }}</ref> A [[glycophosphatidylinositol]] (GPI) membrane anchor at the COOH-terminal tethers PrP to [[cell membrane]]s, and this proves to be integral to the transmission of conformational change; secreted PrP lacking the anchor component is unaffected by the infectious isoform.<ref name = "pmid15933194">{{cite journal | vauthors = Chesebro B, Trifilo M, Race R, Meade-White K, Teng C, LaCasse R, Raymond L, Favara C, Baron G, Priola S, Caughey B, Masliah E, Oldstone M | display-authors = 6 | title = Anchorless prion protein results in infectious amyloid disease without clinical scrapie | journal = Science | volume = 308 | issue = 5727 | pages = 1435–91435–1439 | date = June 2005 | pmid = 15933194 | doi = 10.1126/science.1110837 | s2cid = 10064966 | citeseerx = 10.1.1.401.781 | bibcode = 2005Sci...308.1435C | s2cid = 10064966 }}</ref>

PrP [[messenger RNA]] contains a [[pseudoknot]] structure ([[prion pseudoknot]]), which is thought to be involved in regulation of PrP [[Protein biosynthesis#Translation|protein translation]].<ref>{{cite journal | vauthors = Barrette I, Poisson G, Gendron P, Major F | title = Pseudoknots in prion protein mRNAs confirmed by comparative sequence analysis and pattern searching | journal = Nucleic Acids ResResearch | volume = 29 | issue = 3 | pages = 753–758 | yeardate = February 2001 | pmid = 11160898 | pmc = 30388 | doi = 10.1093/nar/29.3.753 }}</ref>

The mechanism for conformational conversion to the scrapie isoform is speculated to be an elusive [[ligand]]-protein, but, so far, no such compound has been identified. However, a large body of research has developed on candidates and their interaction with the PrP^C.<ref name = "review1">{{cite journal | vauthors = Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR | title = Physiology of the prion protein | journal = Physiol.Physiological Rev.Reviews | volume = 88 | issue = 2 | pages = 673–728 | date = April 2008 | pmid = 18391177 | doi = 10.1152/physrev.00007.2007 }}</ref>

[[Copper]], [[zinc]], [[manganese]], and [[nickel]] are confirmed PrP ligands that bind to its octarepeat region.<ref name = "Human PrP Heavy metals">{{cite journal | vauthors = Prčina M, Kontseková E, Novák M | title = Prion protein prevents heavy metals overloading of cells and thus protects them against their toxicity | journal = Acta Virol.Virologica | volume = 59 | issue = 2 | pages = 179–84179–184 | yeardate = June 2015 | pmid = 26104335 | doi = 10.4149/av_2015_02_179 | doi-access = free }}</ref> Ligand binding causes a conformational change with unknown effect. Heavy metal binding at PrP has been linked to resistance to [[oxidative stress]] arising from [[heavy metal toxicity]].<ref name = "Human PrP Heavy metals"/><ref name = "pmid11145979">{{cite journal | vauthors = Brown DR, Clive C, Haswell SJ | title = Antioxidant activity related to copper binding of native prion protein | journal = J.Journal Neurochem.of Neurochemistry | volume = 76 | issue = 1 | pages = 69–76 | date = January 2001 | pmid = 11145979 | doi = 10.1046/j.1471-4159.2001.00009.x | s2cid = 45647133 | doi-access = free }}</ref>

Although theThe precise function of PrP is not yet known,. itIt ismay play possiblya involvedrole in the transport of [[ion]]ic copper tointo cells from the surrounding environment. Researchers have also proposed roles for PrP in cell signaling or in the formation of [[synapse]]s.<ref>{{cite journal | vauthors = Kanaani J, Prusiner SB, Diacovo J, Baekkeskov S, Legname G | title = Recombinant prion protein induces rapid polarization and development of synapses in embryonic rat hippocampal neurons in vitro | journal = Journal of Neurochemistry | volume = 95 | issue = 5 | pages = 1373–861373–1386 | date = December 2005 | pmid = 16313516 | doi = 10.1111/j.1471-4159.2005.03469.x | s2cid = 24329326 | doi-access = free }}</ref> PrP^C attaches to the outer surface of the [[cell membrane]] by a [[glycosylphosphatidylinositol]] anchor at its [[C-terminal]] [[serine|Ser]]231.

[[Prion protein]] contains five [[peptide|octapeptide]] repeats with sequence PHGGGWGQ (though the first repeat has the slightly- modified, [[histidine]]-deficient sequence PQGGGGWGQ). This is thought to generate a copper-[[binding domain]] via nitrogen atoms in the histidine [[imidazole]] [[Side chain|side-chains]] and deprotonated [[amide]] nitrogens from the 2nd and 3rd glycines in the repeat. The ability to bind copper is, therefore, [[pH]]-dependent. [[Nuclear magnetic resonance|NMR]] shows copper binding results in a [[Protein structure|conformational]] change at the [[N-terminus]].

PrP^Sc is a conformational isoform of PrP^C, but this orientation tends to accumulate in compact, [[protease]]-resistant aggregates within neural tissue.<ref name = "pmid15272267">{{cite journal | vauthors = Ross CA, Poirier MA | title = Protein aggregation and neurodegenerative disease | journal = Nat.Nature Med.Medicine | volume = 10 Suppl | issue = 7 Suppl | pages = S10–7S10–S17 | date = July 2004 | pmid = 15272267 | doi = 10.1038/nm1066 | s2cid = 205383483 }}</ref> The abnormal PrP^Sc isoform has a different [[secondary structure|secondary]] and [[tertiary structure]] from PrP^C, but identical primary sequence. [[Circular dichroism]] shows that normalWhereas PrP^C has 42%largely [[alpha helix|alpha helical]] and 3%disordered [[betadomains,<ref>{{cite sheet]]journal content| vauthors = Riek R, whereasHornemann S, Wider G, Glockshuber R, Wüthrich K | title = NMR characterization of the full-length recombinant murine prion protein, mPrP(23-231) | journal = FEBS Letters | volume = 413 | issue = 2 | pages = 282–288 | date = August 1997 | pmid = 9280298 | doi = 10.1016/S0014-5793(97)00920-4 | bibcode = 1997FEBSL.413..282R | s2cid = 39791520 | url = https://www.zora.uzh.ch/id/eprint/191727/1/S0014-5793%2897%2900920-4.pdf }}</ref> PrP^Sc ishas only 30%no alpha helix and 43%an amyloid fibril core composed of a stack of PrP molecules glued together by parallel in-register intermolecular beta sheetsheets.<ref name = "pmid7902575">{{cite journal | vauthors = PanKraus KMA, BaldwinHoyt MF, NguyenSchwartz JCL, GassetHansen MB, SerbanArtikis AE, GrothHughson DAG, MehlhornRaymond IGJ, HuangRace ZB, FletterickBaron RJGS, CohenCaughey FEB | titledisplay-authors = Conversion6 of| alpha-helicestitle into= betaHigh-sheetsresolution featuresstructure inand thestrain formationcomparison of theinfectious scrapie prionmammalian proteinsprions | journal = Proc.Molecular Natl. Acad. Sci. U.S.A.Cell | volume = 9081 | issue = 2321 | pages = 10962–64540–4551.e6 | date = DecemberNovember 19932021 | pmid = 7902575 | pmc = 4790134433091 | doi = 10.10731016/pnasj.90molcel.232021.10962|08.011 bibcode}}</ref><ref>{{cite = 1993PNAS...9010962Pjournal | doi-accessvauthors = free }}</ref>Manka HoweverSW, theZhang presenceW, ofWenborn alphaA, helicesBetts inJ, infectiousJoiner PrP^ScS, hasSaibil comeHR, intoCollinge questionJ, withWadsworth currentJD models| proposingdisplay-authors a= lack6 of| alphatitle helices= altogether,2.7 replacedÅ insteadcryo-EM withstructure aof totalex betavivo sheetRML composition.<ref>{{Citeprion fibrils journal|last1 journal =Baskakov Nature Communications |first1 volume =Ilia V.13 |last2 issue =Caughey 1 |first2 pages =Byron 4004 |last3 date =Requena July 2022 |first3 pmid =Jesús R.35831275 |last4 pmc =Sevillano 9279362 |first4 doi =Alejandro M10.1038/s41467-022-30457-7 |last5 bibcode =Surewicz 2022NatCo..13.4004M }}</ref><ref>{{cite journal |first5 vauthors =Witold Hoyt F, Standke HG, Artikis E, Schwartz CL, Hansen B, Li K., Hughson AG, Manca M, Thomas OR, Raymond GJ, Race B, Baron GS, Caughey B, Kraus A |last6 display-authors =Wille|first6=Holger|date=2019-01-01 6 | title =The Cryo-EM structure of anchorless RML prion 2018reveals roundvariations tablesin (I):shared themotifs structurebetween ofdistinct strains PrPSc| journal =Prion Nature Communications | volume = 13 | issue = 1 | pages =46–52 4005 | date = July 2022 | pmid = 35831291 | pmc = 9279418 | doi = 10.10801038/19336896.2019.1569450|issn=1933s41467-6896022-30458-6 |pmid bibcode =30646817|pmc=6422368 2022NatCo..13.4005H }}</ref> This refolding renders the PrP^Sc isoform extremely resistant to [[proteolysis]].

The propagation of PrP^Sc is a topic of great interest, as its accumulation is a pathological cause of [[neurodegeneration]]. Based on the progressive nature of spongiform encephalopathies, the predominant hypothesis posits that the change from normal PrP^C is caused by the presence and interaction with PrP^Sc.<ref name = "pmid21350487">{{cite journal | vauthors = Sandberg MK, Al-Doujaily H, Sharps B, Clarke AR, Collinge J | title = Prion propagation and toxicity in vivo occur in two distinct mechanistic phases | journal = Nature | volume = 470 | issue = 7335 | pages = 540–2540–542 | date = February 2011 | pmid = 21350487 | doi = 10.1038/nature09768 | s2cid = 4399936 | bibcode = 2011Natur.470..540S | s2cid = 4399936 }}</ref> Strong support for this is taken from studies in which ''PRNP''-knockout mice are resistant to the introduction of PrP^Sc.<ref name = "pmid8100741">{{cite journal | vauthors = Büeler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C | title = Mice devoid of PrP are resistant to scrapie | journal = Cell | volume = 73 | issue = 7 | pages = 1339–471339–1347 | date = July 1993 | pmid = 8100741 | doi = 10.1016/0092-8674(93)90360-3 | doi-access = free }}</ref> Despite widespread acceptance of the conformation conversion hypothesis, some studies mitigate claims for a direct link between PrP^Sc and [[cytotoxicity]].<ref name = "elusive">{{cite journal | vauthors = Aguzzi A, Baumann F, Bremer J | title = The prion's elusive reason for being | journal = Annu.Annual Rev.Review Neurosci.of Neuroscience | volume = 31 | pages = 439–77439–477 | year = 2008 | pmid = 18558863 | doi = 10.1146/annurev.neuro.31.060407.125620 }}</ref>

The strong association to neurodegenerative diseases raises many questions of the function of PrP in the brain. A common approach is using PrP-knockout and [[transgenic]] mice to investigate deficiencies and differences.<ref name = "pmid14522848">{{cite journal | vauthors = Weissmann C, Flechsig E | title = PrP knock-out and PrP transgenic mice in prion research | journal = Br.British Med.Medical Bull.Bulletin | volume = 66 | pages = 43–60 | year = 2003 | pmid = 14522848 | doi = 10.1093/bmb/66.1.43 | doi-access = free }}</ref> Initial attempts produced two strains of PrP-null mice that show no physiological or developmental differences when subjected to an array of tests. However, more recent strains have shown significant cognitive abnormalities.<ref name = "review1"/>

As the null mice age, a marked loss of [[Purkinje cells]] in the [[cerebellum]] results in decreased motor coordination. However, this effect is not a direct result of PrP's absence, and rather arises from increased [[PRND|Doppel]] gene expression.<ref name = "pmid9876879">{{cite journal | vauthors = Katamine S, Nishida N, Sugimoto T, Noda T, Sakaguchi S, Shigematsu K, Kataoka Y, Nakatani A, Hasegawa S, Moriuchi R, Miyamoto T | display-authors = 6 | title = Impaired motor coordination in mice lacking prion protein | journal = Cell.Cellular Mol.and Neurobiol.Molecular Neurobiology | volume = 18 | issue = 6 | pages = 731–42731–742 | date = December 1998 | pmid = 9876879 | doi = 10.1023/A:1020234321879 | s2cid = 23409873 }}</ref> Other observed differences include reduced stress response and increased exploration of novel environments.<ref name = "pmid15970215">{{cite journal | vauthors = Nico PB, de-Paris F, Vinadé ER, Amaral OB, Rockenbach I, Soares BL, Guarnieri R, Wichert-Ana L, Calvo F, Walz R, Izquierdo I, Sakamoto AC, Brentani R, Martins VR, Bianchin MM | display-authors = 6 | title = Altered behavioural response to acute stress in mice lacking cellular prion protein | journal = Behav.Behavioural Brain Res.Research | volume = 162 | issue = 2 | pages = 173–81173–181 | date = July 2005 | pmid = 15970215 | doi = 10.1016/j.bbr.2005.02.003 | s2cid = 37511702 }}</ref><ref name = "pmid10521590">{{cite journal | vauthors = Roesler R, Walz R, Quevedo J, de-Paris F, Zanata SM, Graner E, Izquierdo I, Martins VR, Brentani RR | display-authors = 6 | title = Normal inhibitory avoidance learning and anxiety, but increased locomotor activity in mice devoid of PrP(C) | journal = Brain ResResearch. Mol.Molecular Brain Res.Research | volume = 71 | issue = 2 | pages = 349–53349–353 | date = August 1999 | pmid = 10521590 | doi = 10.1016/S0169-328X(99)00193-X }}</ref>

[[Circadian rhythm]] is altered in null mice.<ref name = "review2"/> [[Fatal familial insomnia]] is thought to be the result of a point mutation in ''PRNP'' at codon 178, which corroborates PrP's involvement in sleep-wake cycles.<ref name = "pmid1346338">{{cite journal | vauthors = Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY, Xue R, Leal S, Montagna P, Cortelli P | display-authors = 6 | title = Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene | journal = N.The Engl.New J.England Med.Journal of Medicine | volume = 326 | issue = 7 | pages = 444–9444–449 | date = February 1992 | pmid = 1346338 | pmc = 6151859 | doi = 10.1056/NEJM199202133260704 }}</ref> In addition, circadian regulation has been demonstrated in PrP mRNA, which cycles regularly with day-night.<ref name = "pmid10391428">{{cite journal | vauthors = Cagampang FR, Whatley SA, Mitchell AL, Powell JF, Campbell IC, Coen CW | title = Circadian regulation of prion protein messenger RNA in the rat forebrain: a widespread and synchronous rhythm | journal = Neuroscience | volume = 91 | issue = 4 | pages = 1201–41201–1204 | year = 1999 | pmid = 10391428 | doi = 10.1016/S0306-4522(99)00092-5 | s2cid = 42892475 }}</ref>

While null mice exhibit normal learning ability and [[short-term memory]], [[long-term memory]] consolidation deficits have been demonstrated. As with [[ataxia]], this is attributable to Doppel gene expression. However, [[spatial learning]], a predominantly hippocampal-function, is decreased in the null mice and can be recovered with the reinstatement of PrP in neurons; this indicates that loss of PrP function is the cause.<ref name = "pmid15837581">{{cite journal | vauthors = Criado JR, Sánchez-Alavez M, Conti B, Giacchino JL, Wills DN, Henriksen SJ, Race R, Manson JC, Chesebro B, Oldstone MB | display-authors = 6 | title = Mice devoid of prion protein have cognitive deficits that are rescued by reconstitution of PrP in neurons | journal = Neurobiol.Neurobiology Dis.of Disease | volume = 19 | issue = 1–2 | pages = 255–65255–265 | year = 2005 | pmid = 15837581 | doi = 10.1016/j.nbd.2005.01.001 | s2cid = 2618712 }}</ref><ref name = "pmid20133875">{{cite journal | vauthors = Balducci C, Beeg M, Stravalaci M, Bastone A, Sclip A, Biasini E, Tapella L, Colombo L, Manzoni C, Borsello T, Chiesa R, Gobbi M, Salmona M, Forloni G | display-authors = 6 | title = Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein | journal = Proc.Proceedings Natl.of Acad.the Sci.National U.S.A.Academy of Sciences of the United States of America | volume = 107 | issue = 5 | pages = 2295–3002295–2300 | date = February 2010 | pmid = 20133875 | pmc = 2836680 | doi = 10.1073/pnas.0911829107 | doi-access = free | bibcode = 2010PNAS..107.2295B | doi-access = free }}</ref> The interaction of hippocampal PrP with [[laminin]] (LN) is pivotal in memory processing and is likely modulated by the [[kinases]] PKA and ERK1/2.<ref name = "pmid17156386">{{cite journal | vauthors = Coitinho AS, Freitas AR, Lopes MH, Hajj GN, Roesler R, Walz R, Rossato JI, Cammarota M, Izquierdo I, Martins VR, Brentani RR | display-authors = 6 | title = The interaction between prion protein and laminin modulates memory consolidation | journal = Eur.The J.European Neurosci.Journal of Neuroscience | volume = 24 | issue = 11 | pages = 3255–643255–3264 | date = December 2006 | pmid = 17156386 | doi = 10.1111/j.1460-9568.2006.05156.x | s2cid = 17164351 }}</ref><ref name = "pmid15931169">{{cite journal | vauthors = Shorter J, Lindquist S | title = Prions as adaptive conduits of memory and inheritance | journal = Nat.Nature RevReviews. Genet.Genetics | volume = 6 | issue = 6 | pages = 435–50435–450 | date = June 2005 | pmid = 15931169 | doi = 10.1038/nrg1616 | s2cid = 5575951 }}</ref>

Further support for PrP's role in memory formation is derived from several population studies. A test of healthy young humans showed increased long-term memory ability associated with an MM or MV genotype when compared to VV.<ref name = "pmid15987701">{{cite journal | vauthors = Papassotiropoulos A, Wollmer MA, Aguzzi A, Hock C, Nitsch RM, de Quervain DJ | title = The prion gene is associated with human long-term memory | journal = Hum.Human Mol.Molecular Genet.Genetics | volume = 14 | issue = 15 | pages = 2241–62241–2246 | date = August 2005 | pmid = 15987701 | doi = 10.1093/hmg/ddi228| url = http://doc.rero.ch/record/297873/files/ddi228.pdf | doi-access = free }}</ref> [[Down syndrome]] patients with a single [[valine]] substitution have been linked to earlier cognitive decline.<ref name = "pmid12796830">{{cite journal | vauthors = Del Bo R, Comi GP, Giorda R, Crimi M, Locatelli F, Martinelli-Boneschi F, Pozzoli U, Castelli E, Bresolin N, Scarlato G | display-authors = 6 | title = The 129 codon polymorphism of the prion protein gene influences earlier cognitive performance in Down syndrome subjects | journal = J.Journal Neurol.of Neurology | volume = 250 | issue = 6 | pages = 688–92688–692 | date = June 2003 | pmid = 12796830 | doi = 10.1007/s00415-003-1057-5 | s2cid = 21049364 }}</ref> Several [[Polymorphism (biology)|polymorphisms]] in ''PRNP'' have been linked with cognitive impairment in the elderly as well as earlier cognitive decline.<ref name = "pmid9748018">{{cite journal | vauthors = Berr C, Richard F, Dufouil C, Amant C, Alperovitch A, Amouyel P | title = Polymorphism of the prion protein is associated with cognitive impairment in the elderly: the EVA study | journal = Neurology | volume = 51 | issue = 3 | pages = 734–7734–737 | date = September 1998 | pmid = 9748018 | doi = 10.1212/wnl.51.3.734 | s2cid = 11352163 }}</ref><ref name = "pmid12891686">{{cite journal | vauthors = Croes EA, Dermaut B, Houwing-Duistermaat JJ, Van den Broeck M, Cruts M, Breteler MM, Hofman A, van Broeckhoven C, van Duijn CM | display-authors = 6 | title = Early cognitive decline is associated with prion protein codon 129 polymorphism | journal = Ann.Annals Neurol.of Neurology | volume = 54 | issue = 2 | pages = 275–6275–276 | date = August 2003 | pmid = 12891686 | doi = 10.1002/ana.10658 | s2cid = 31538672 }}</ref><ref name = "pmid16023289">{{cite journal | vauthors = Kachiwala SJ, Harris SE, Wright AF, Hayward C, Starr JM, Whalley LJ, Deary IJ | title = Genetic influences on oxidative stress and their association with normal cognitive ageing | journal = Neurosci.Neuroscience Lett.Letters | volume = 386 | issue = 2 | pages = 116–20116–120 | date = September 2005 | pmid = 16023289 | doi = 10.1016/j.neulet.2005.05.067 | s2cid = 23642220 }}</ref> All of these studies investigated differences in codon 129, indicating its importance in the overall functionality of PrP, in particular with regard to memory.

PrP is present in both the pre- and post-synaptic compartments, with the greatest concentration in the pre-synaptic portion.<ref name = "pmid10516306">{{cite journal | vauthors = Herms J, Tings T, Gall S, Madlung A, Giese A, Siebert H, Schürmann P, Windl O, Brose N, Kretzschmar H | display-authors = 6 | title = Evidence of presynaptic location and function of the prion protein | journal = J.The Neurosci.Journal of Neuroscience | volume = 19 | issue = 20 | pages = 8866–758866–8875 | date = October 1999 | pmid = 10516306 | pmc = 6782778 | doi = 10.1523/JNEUROSCI.19-20-08866.1999| pmc = 6782778 | doi-access = free }}</ref> Considering this and PrP's suite of behavioral influences, the neural cell functions and interactions are of particular interest. Based on the copper ligand, one proposed function casts PrP as a copper buffer for the [[synaptic cleft]]. In this role, the protein could serve as either a copper [[homeostasis]] mechanism, a calcium modulator, or a sensor for copper or oxidative stress.<ref name = "pmid2549468">{{cite journal | vauthors = Kardos J, Kovács I, Hajós F, Kálmán M, Simonyi M | title = Nerve endings from rat brain tissue release copper upon depolarization. A possible role in regulating neuronal excitability | journal = Neurosci.Neuroscience Lett.Letters | volume = 103 | issue = 2 | pages = 139–44139–144 | date = August 1989 | pmid = 2549468 | doi = 10.1016/0304-3940(89)90565-X | s2cid = 24917999 }}</ref> Loss of PrP function has been linked to [[long-term potentiation]] (LTP). This effect can be positive or negative and is due to changes in neuronal excitability and synaptic transmission in the [[hippocampus]].<ref name = "pmid15450159">{{cite journal | vauthors = Bailey CH, Kandel ER, Si K | title = The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth | journal = Neuron | volume = 44 | issue = 1 | pages = 49–57 | date = September 2004 | pmid = 15450159 | doi = 10.1016/j.neuron.2004.09.017 | s2cid = 2637074 | doi-access = free }}</ref><ref name = "pmid16805766">{{cite journal | vauthors = Barco A, Bailey CH, Kandel ER | title = Common molecular mechanisms in explicit and implicit memory | journal = J.Journal Neurochem.of Neurochemistry | volume = 97 | issue = 6 | pages = 1520–331520–1533 | date = June 2006 | pmid = 16805766 | doi = 10.1111/j.1471-4159.2006.03870.x | s2cid = 26307975 | doi-access = free }}</ref>

Some research indicates PrP involvement in neuronal development, differentiation, and [[neurite]] outgrowth. The PrP-activated signal transduction pathway is associated with axon and dendritic outgrowth with a series of kinases.<ref name = "elusive"/><ref name = "pmid19242475">{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–321128–1132 | date = February 2009 | pmid = 19242475 | pmc = 2748841 | doi = 10.1038/nature07761 | bibcode = 2009Natur.457.1128L }}</ref>

Though most attention is focused on PrP's presence in the nervous system, it is also abundant in immune system tissue. PrP immune cells include hematopoietic stem cells, mature lymphoid and myeloid compartments, and certain [[lymphocytes]]; also, it has been detected in [[natural killer cells]], [[platelets]], and [[monocytes]]. [[T cell]] activation is accompanied by a strong up-regulation of PrP, though it is not requisite. The lack of immunoresponse to [[transmissible spongiform encephalopathy|transmissible spongiform encephalopathies]] (TSE), neurodegenerative diseases caused by prions, could stem from the tolerance for PrP^Sc.<ref name = "pmid16968391">{{cite journal | vauthors = Isaacs JD, Jackson GS, Altmann DM | title = The role of the cellular prion protein in the immune system | journal = Clin.Clinical Exp.and Immunol.Experimental Immunology | volume = 146 | issue = 1 | pages = 1–8 | date = October 2006 | pmid = 16968391 | pmc = 1809729 | doi = 10.1111/j.1365-2249.2006.03194.x }}</ref>

More than 20 mutations in the ''PRNP'' gene have been identified in people with inherited [[prion disease]]s, which include the following:<ref name = "pmid15354870">{{cite journal | vauthors = Castilla J, Hetz C, Soto C | title = Molecular mechanisms of neurotoxicity of pathological prion protein | journal = CurrCurrent MolMolecular MedMedicine | volume = 4 | issue = 4 | pages = 397–403 | yeardate = June 2004 | pmid = 15354870 | doi = 10.2174/1566524043360654 }}</ref><ref name = "pmid12420099">{{cite journal | vauthors = Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H | title = Mutations of the prion protein gene phenotypic spectrum | journal = JJournal Neurolof Neurology | volume = 249 | issue = 11 | pages = 1567–821567–1582 | yeardate = November 2002 | pmid = 12420099 | doi = 10.1007/s00415-002-0896-9 | s2cid = 22688729 }}</ref>

* [[Gerstmann–Sträussler–Scheinker syndrome]] – usually a change in [[codon]] 102 from [[proline]] to [[leucine]]<ref name = "pmid11535002">{{cite journal | vauthors = Collins S, McLean CA, Masters CL | title = Gerstmann-StrausslerSträussler-Scheinker syndrome, fatal familial insomnia, and kuru: a review of these less common human transmissible spongiform encephalopathies | journal = JJournal Clinof Clinical NeurosciNeuroscience | volume = 8 | issue = 5 | pages = 387–97387–397 | yeardate = September 2001 | pmid = 11535002 | doi = 10.1054/jocn.2001.0919 | s2cid = 31976428 }}</ref>

* [[fatal familial insomnia]] – [[aspartic acid]]-178 is replaced by [[asparagine]] while [[methionine]] is present at amino acid 129<ref name = "pmid12849238">{{cite journal | vauthors = Montagna P, Gambetti P, Cortelli P, Lugaresi E | title = Familial and sporadic fatal insomnia | journal = The Lancet. NeurolNeurology | volume = 2 | issue = 3 | pages = 167–76167–176 | yeardate = March 2003 | pmid = 12849238 | doi = 10.1016/S1474-4422(03)00323-5 | s2cid = 20822956 }}</ref>

Several other changes in the ''PRNP'' gene (called polymorphisms) do not cause prion diseases but may affect a person's risk of developing these diseases or alter the course of the disorders. An [[allele]] that codes for a PRNP variant, G127V, provides resistance to [[Kuru (disease)|kuru]].<ref>{{cite journal | vauthors = Mead S, Whitfield J, Poulter M, Shah P, Uphill J, Campbell T, Al-Dujaily H, Hummerich H, Beck J, Mein CA, Verzilli C, Whittaker J, Alpers MP, Collinge J | display-authors = 6 | title = A Novelnovel Protectiveprotective Prionprion Proteinprotein Variantvariant that Colocalizescolocalizes with Kurukuru Exposureexposure | journal = The New England Journal of Medicine | volume = 361 | issue = 21 | pages = 2056–2065 | yeardate = November 2009 | pmid = 19923577 | doi = 10.1056/NEJMoa0809716 | urldoi-access = http://researchonline.lshtm.ac.uk/4514/1/nejmoa0809716.pdffree }}

In addition, some prion diseases can be transmitted from external sources of PrP^Sc.<ref name = "pmid19308092">{{cite journal | vauthors = Hwang D, Lee IY, Yoo H, Gehlenborg N, Cho JH, Petritis B, Baxter D, Pitstick R, Young R, Spicer D, Price ND, Hohmann JG, Dearmond SJ, Carlson GA, Hood LE | display-authors = 6 | title = A systems approach to prion disease | journal = Mol.Molecular Syst.Systems Biol.Biology | volume = 5 | issue = 1 | pages = 252 | year = 2009 | pmid = 19308092 | pmc = 2671916 | doi = 10.1038/msb.2009.10 }}</ref>

PrP^C protein is one of several cellular receptors of soluble [[amyloid beta]] (Aβ) oligomers, which are canonically implicated in causing [[Alzheimer's disease]].<ref name= "Laurén_2014" >{{cite journal | vauthors = Laurén J | title = Cellular prion protein as a therapeutic target in Alzheimer's disease | journal = Journal of Alzheimer's Disease | volume = 38 | issue = 2 | pages = 227–244 | date = 2014 | pmid = 23948943 | doi = 10.3233/JAD-130950 }}</ref> These [[oligomer]]s are composed of smaller Aβ plaques, and are the most damaging to the integrity of a [[neuron]].<ref name="Laurén_2014" /> The precise mechanism of soluble Aβ oligomers directly inducing [[neurotoxicity]] is unknown, and experimental deletion of ''PRNP'' in animals has yielded several conflicting findings. When Aβ oligomers were injected into the [[Ventricular system|cerebral ventricles]] of a mouse model of Alzheimer's, ''PRNP'' deletion did not offer protection, only anti-PrP^C antibodies prevented long-term memory and [[spatial learning]] deficits.<ref name= "Zhou_2013" >{{cite journal | vauthors = Zhou J, Liu B | title = Alzheimer's disease and prion protein | journal = Intractable & Rare Diseases Research | volume = 2 | issue = 2 | pages = 35–44 | date = May 2013 | pmid = 25343100 | pmc = 4204584 | doi = 10.5582/irdr.2013.v2.2.35 | pmc=4204584}}</ref><ref name= "Laurén_2009" >{{cite journal | vauthors = Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM | title = Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers | journal = Nature | volume = 457 | issue = 7233 | pages = 1128–1132 | date = FebFebruary 2009 | pmid = 19242475 | pmc = 2748841 | doi = 10.1038/nature07761 | pmc=2748841 | bibcode = 2009Natur.457.1128L }}</ref> This would suggest either an unequal relation between PRNP and Aβ oligomer-mediated [[neurodegeneration]] or a site-specific relational significance. In the case of direct injection of Aβ oligomers into the [[hippocampus]], ''PRNP''-knockout mice were found to be indistinguishable from control with respect to both neuronal death rates and measurements of [[synaptic plasticity]].<ref name="Laurén_2014" /><ref name="Laurén_2009" /> It was further found that Aβ-oligomers bind to PrP^C at the [[postsynaptic density]], indirectly overactivating the [[NMDA receptor]] via the [[FYN|Fyn]] enzyme, resulting in [[excitotoxicity]].<ref name="Zhou_2013" /> Soluble Aβ oligomers also bind to PrP^C at the [[dendritic spines]], forming a complex with Fyn and excessively activating [[Tau protein|tau]], another protein implicated in Alzheimer's.<ref name="Zhou_2013" /> As the gene [[FYN]] codes for the enzyme Fyn, FYN-knockout mice display neither [[excitotoxic]] events nor [[dendritic spine|dendritic spine shrinkage]] when injected with Aβ oligomers.<ref name="Zhou_2013" /> In mammals, the full functional significance of PRNP remains unclear, as ''PRNP'' deletion has been prophylactically implemented by the cattle industry without apparent harm.<ref name="Laurén_2014" /> In mice, this same deletion [[phenotypically]] varies between Alzheimer's mouse lines, as hAPPJ20 mice and TgCRND8 mice show a slight increase in [[epileptic]] activity, contributing to conflicting results when examining Alzheimer's survival rates.<ref name="Laurén_2014" /> Of note, the deletion of ''PRNP'' in both APPswe and SEN1dE9, two other [[transgenic]] models of Alzheimer's, attenuated the epilepsy-induced death phenotype seen in a subset of these animals.<ref name="Laurén_2014" /> Taken collectively, recent evidence suggests PRNP may be important for conducing the neurotoxic effects of soluble Aβ-oligomers and the emergent disease state of Alzheimer's.<ref name="Laurén_2014" /><ref name="Zhou_2013" /><ref name="Laurén_2009" />

In humans, the [[methionine]]/[[valine]] [[Genetic polymorphism|polymorphism]] at [[codon]] 129 of ''PRNP'' (rs1799990) is most closely associated with Alzheimer's disease.<ref name="He_2013">{{cite journal | vauthors = He J, Li X, Yang J, Huang J, Fu X, Zhang Y, Fan H | title = The association between the methionine/valine (M/V) polymorphism (rs1799990) in the PRNP gene and the risk of Alzheimer disease: an update by meta-analysis | journal = Journal of the Neurological Sciences | volume = 326 | issue = 1–2 | pages = 89–95 | date = MarMarch 2013 | pmid = 23399523 | doi = 10.1016/j.jns.2013.01.020 | s2cid = 31070331 }}</ref> Variant V [[allele]] carriers (VV and MV) show a 13% decreased risk with respect to developing Alzheimer's compared to the methionine [[homozygote]] (MM). However, the protective effects of variant V carriers have been found exclusively in [[Caucasian race|Caucasians]]. The decreased risk in V allele carriers is further limited to late-onset Alzheimer's disease only (≥ 65 years).<ref name="He_2013" /> PRNP can also functionally interact with polymorphisms in two other genes implicated in Alzheimer's, [[PSEN1]] and [[Apolipoprotein E|APOE]], to compound risk for both Alzheimer's and [[Creutzfeldt–Jakob disease|sporadic Creutzfeldt–Jakob disease]].<ref name="Laurén_2014" /> A [[point mutation]] on codon 102 of ''PRNP'' at least in part contributed to three separate patients' atypical [[frontotemporal dementia]] within the same family, suggesting a new phenotype for [[Gerstmann–Sträussler–Scheinker syndrome]].<ref name="Laurén_2014" /><ref name="Giovagnoli_2008">{{cite journal | vauthors = Giovagnoli AR, Di Fede G, Aresi A, Reati F, Rossi G, Tagliavini F | title = Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family | journal = Neurological Sciences | volume = 29 | issue = 6 | pages = 405–10405–410 | date = December 2008 | pmid = 19030774 | doi = 10.1007/s10072-008-1025-z | s2cid = 20553167 }}</ref> The same study proposed sequencing ''PRNP'' in cases of ambiguously diagnosed dementia, as the various forms of [[dementia]] can prove challenging to [[Differential diagnosis|differentially diagnose]].<ref name="Giovagnoli_2008" />

A strong [[Protein-protein interaction|interaction]] exists between PrP and the [[cochaperone]] [[Hop (protein)|Hop]] ([[HSP70|Hsp70]]/[[HSP90|Hsp90]] organizing protein; also called STI1 (Stress-induced protein 1)).<ref name = "pmid17498662">{{cite journal | vauthors = Americo TA, Chiarini LB, Linden R | title = Signaling induced by hop/STI-1 depends on endocytosis | journal = Biochem.Biochemical Biophys.and Res.Biophysical Commun.Research Communications | volume = 358 | issue = 2 | pages = 620–5620–625 | date = June 2007 | pmid = 17498662 | doi = 10.1016/j.bbrc.2007.04.202 }}</ref><ref name = pmid12093732>{{cite journal | vauthors = Zanata SM, Lopes MH, Mercadante AF, Hajj GN, Chiarini LB, Nomizo R, Freitas AR, Cabral AL, Lee KS, Juliano MA, de Oliveira E, Jachieri SG, Burlingame A, Huang L, Linden R, Brentani RR, Martins VR | display-authors = 6 | title = Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection | journal = The EMBO J.Journal | volume = 21 | issue = 13 | pages = 3307–163307–3316 | date = JulJuly 2002 | pmid = 12093732 | pmc = 125391 | doi = 10.1093/emboj/cdf325 }}</ref>