{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T23:53:45Z","timestamp":1786406025378,"version":"build-2736575974"},"reference-count":101,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T00:00:00Z","timestamp":1598572800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Number 18K07499"],"award-info":[{"award-number":["KAKENHI Grant Number 18K07499"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["KAKENHI Grant Number 19H03548"],"award-info":[{"award-number":["KAKENHI Grant Number 19H03548"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012131","name":"Brain Science Foundation","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/100012131","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Ichiro Kanehara Foundation","award":["-"],"award-info":[{"award-number":["-"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The normal cellular isoform of prion protein, designated PrPC, is constitutively converted to the abnormally folded, amyloidogenic isoform, PrPSc, in prion diseases, which include Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. PrPC is a membrane glycoprotein consisting of the non-structural N-terminal domain and the globular C-terminal domain. During conversion of PrPC to PrPSc, its 2\/3 C-terminal region undergoes marked structural changes, forming a protease-resistant structure. In contrast, the N-terminal region remains protease-sensitive in PrPSc. Reverse genetic studies using reconstituted PrPC-knockout mice with various mutant PrP molecules have revealed that the N-terminal domain has an important role in the normal function of PrPC and the conversion of PrPC to PrPSc. The N-terminal domain includes various characteristic regions, such as the positively charged residue-rich polybasic region, the octapeptide repeat (OR) region consisting of five repeats of an octapeptide sequence, and the post-OR region with another positively charged residue-rich polybasic region followed by a stretch of hydrophobic residues. We discuss the normal functions of PrPC, the conversion of PrPC to PrPSc, and the neurotoxicity of PrPSc by focusing on the roles of the N-terminal regions in these topics.<\/jats:p>","DOI":"10.3390\/ijms21176233","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T09:17:08Z","timestamp":1598606228000},"page":"6233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["N-Terminal Regions of Prion Protein: Functions and Roles in Prion Diseases"],"prefix":"10.3390","volume":"21","author":[{"given":"Hideyuki","family":"Hara","sequence":"first","affiliation":[{"name":"Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suehiro","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Division of Molecular Neurobiology, The Institute for Enzyme Research (KOSOKEN), Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1146\/annurev.neuro.31.060407.125620","article-title":"The prion\u2019s elusive reason for being","volume":"31","author":"Aguzzi","year":"2008","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1111\/j.1750-3639.1998.tb00171.x","article-title":"The prion diseases","volume":"8","author":"Prusiner","year":"1998","journal-title":"Brain Pathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/s41576-018-0011-4","article-title":"Prions, prionoids and protein misfolding disorders","volume":"19","author":"Scheckel","year":"2018","journal-title":"Nat. Rev. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Giles, K., Olson, S.H., and Prusiner, S.B. (2017). Developing Therapeutics for PrP Prion Diseases. Cold Spring Harb. Perspect. Med., 7.","DOI":"10.1101\/cshperspect.a023747"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Prusiner, S.B. (2004). Early evidence that a protease-resistant protein is an active component of the infectious prion. Cell, 116.","DOI":"10.1016\/S0092-8674(03)01032-8"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1126\/science.6801762","article-title":"Novel proteinaceous infectious particles cause scrapie","volume":"216","author":"Prusiner","year":"1982","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Igel-Egalon, A., Bohl, J., Moudjou, M., Herzog, L., Reine, F., Rezaei, H., and Beringue, V. (2019). Heterogeneity and Architecture of Pathological Prion Protein Assemblies: Time to Revisit the Molecular Basis of the Prion Replication Process?. Viruses, 11.","DOI":"10.3390\/v11050429"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/0092-8674(93)90360-3","article-title":"Mice devoid of PrP are resistant to scrapie","volume":"73","author":"Bueler","year":"1993","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"10608","DOI":"10.1073\/pnas.90.22.10608","article-title":"Ablation of the prion protein (PrP) gene in mice prevents scrapie and facilitates production of anti-PrP antibodies","volume":"90","author":"Prusiner","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","first-page":"331","article-title":"PrP gene dosage determines the timing but not the final intensity or distribution of lesions in scrapie pathology","volume":"3","author":"Manson","year":"1994","journal-title":"Neurodegeneration"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"7586","DOI":"10.1128\/jvi.69.12.7586-7592.1995","article-title":"Accumulation of proteinase K-resistant prion protein (PrP) is restricted by the expression level of normal PrP in mice inoculated with a mouse-adapted strain of the Creutzfeldt-Jakob disease agent","volume":"69","author":"Sakaguchi","year":"1995","journal-title":"J. Virol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1006\/jmbi.1994.0030","article-title":"Prion protein gene variation among primates","volume":"245","author":"Schatzl","year":"1995","journal-title":"J. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/0092-8674(85)90333-2","article-title":"A cellular gene encodes scrapie PrP 27\u201330 protein","volume":"40","author":"Oesch","year":"1985","journal-title":"Cell."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1016\/S0014-5793(97)00920-4","article-title":"NMR characterization of the full-length recombinant murine prion protein, mPrP(23\u2013231)","volume":"413","author":"Riek","year":"1997","journal-title":"FEBS Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13452","DOI":"10.1073\/pnas.94.25.13452","article-title":"Structure of the recombinant full-length hamster prion protein PrP(29\u2013231): The N terminus is highly flexible","volume":"94","author":"Donne","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1073\/pnas.0408939102","article-title":"Prion protein NMR structures of chickens, turtles, and frogs","volume":"102","author":"Calzolai","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1126\/science.1675487","article-title":"Molecular biology of prion diseases","volume":"252","author":"Prusiner","year":"1991","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Hackl, S., and Becker, C.F.W. (2019). Prion protein-Semisynthetic prion protein (PrP) variants with posttranslational modifications. J. Pept. Sci., 25.","DOI":"10.1002\/psc.3216"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/0092-8674(87)90150-4","article-title":"Scrapie prion protein contains a phosphatidylinositol glycolipid","volume":"51","author":"Stahl","year":"1987","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5043","DOI":"10.1021\/bi00136a600","article-title":"Glycosylinositol phospholipid anchors of the scrapie and cellular prion proteins contain sialic acid","volume":"31","author":"Stahl","year":"1992","journal-title":"Biochemical"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1152\/physrev.00050.2006","article-title":"In and out of the ER: Protein folding, quality control, degradation, and related human diseases","volume":"87","author":"Hebert","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1038\/nature06384","article-title":"Protein translocation across the eukaryotic endoplasmic reticulum and bacterial plasma membranes","volume":"450","author":"Rapoport","year":"2007","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/febs.14608","article-title":"Endoplasmic reticulum stress signalling - From basic mechanisms to clinical applications","volume":"286","author":"Almanza","year":"2019","journal-title":"FEBS J."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Needham, P.G., Guerriero, C.J., and Brodsky, J.L. (2019). Chaperoning Endoplasmic Reticulum-Associated Degradation (ERAD) and Protein Conformational Diseases. Cold Spring Harb. Perspect. Biol., 11.","DOI":"10.1101\/cshperspect.a033928"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Puig, B., Altmeppen, H.C., Linsenmeier, L., Chakroun, K., Wegwitz, F., Piontek, U.K., Tatzelt, J., Bate, C., Magnus, T., and Glatzel, M. (2019). GPI-anchor signal sequence influences PrPC sorting, shedding and signalling, and impacts on different pathomechanistic aspects of prion disease in mice. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007520"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Wulf, M.A., Senatore, A., and Aguzzi, A. (2017). The biological function of the cellular prion protein: An update. BMC Biol., 15.","DOI":"10.1186\/s12915-017-0375-5"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1083\/jcb.200304140","article-title":"Trafficking of prion proteins through a caveolae-mediated endosomal pathway","volume":"162","author":"Peters","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.tcb.2004.12.002","article-title":"The highways and byways of prion protein trafficking","volume":"15","author":"Campana","year":"2005","journal-title":"Trends Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2557","DOI":"10.1007\/s00018-018-2823-y","article-title":"Cellular mechanisms responsible for cell-to-cell spreading of prions","volume":"75","author":"Vilette","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5141","DOI":"10.1242\/jcs.02627","article-title":"Assigning functions to distinct regions of the N-terminus of the prion protein that are involved in its copper-stimulated, clathrin-dependent endocytosis","volume":"118","author":"Taylor","year":"2005","journal-title":"J. Cell Sci."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Uchiyama, K., Tomita, M., Yano, M., Chida, J., Hara, H., Das, N.R., Nykjaer, A., and Sakaguchi, S. (2017). Prions amplify through degradation of the VPS10P sorting receptor sortilin. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006470"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1042\/BJ20061736","article-title":"The low-density lipoprotein receptor-related protein 1 (LRP1) mediates the endocytosis of the cellular prion protein","volume":"402","author":"Taylor","year":"2007","journal-title":"Biochem. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1038\/356577a0","article-title":"Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein","volume":"356","author":"Bueler","year":"1992","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/BF02780662","article-title":"129\/Ola mice carrying a null mutation in PrP that abolishes mRNA production are developmentally normal","volume":"8","author":"Manson","year":"1994","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1023\/A:1026315006619","article-title":"Prion protein is necessary for latent learning and long-term memory retention","volume":"17","author":"Nishida","year":"1997","journal-title":"Cell Mol. Neurobiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/370295a0","article-title":"Prion protein is necessary for normal synaptic function","volume":"370","author":"Collinge","year":"1994","journal-title":"Nature"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/380639a0","article-title":"Altered circadian activity rhythms and sleep in mice devoid of prion protein","volume":"380","author":"Tobler","year":"1996","journal-title":"Nature"},{"key":"ref_38","first-page":"689","article-title":"A mouse prion protein transgene rescues mice deficient for the prion protein gene from purkinje cell degeneration and demyelination","volume":"79","author":"Nishida","year":"1999","journal-title":"Lab. Investig."},{"key":"ref_39","first-page":"169","article-title":"Late-onset olfactory deficits and mitral cell loss in mice lacking prion protein with ectopic expression of Doppel","volume":"20","author":"Kim","year":"2007","journal-title":"Int. J. Mol. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/nn.2238","article-title":"Olfactory behavior and physiology are disrupted in prion protein knockout mice","volume":"12","author":"Valley","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1073\/pnas.93.6.2403","article-title":"Mice deficient for prion protein exhibit normal neuronal excitability and synaptic transmission in the hippocampus","volume":"93","author":"Lledo","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.neulet.2004.09.030","article-title":"Upregulation of cellular prion protein (PrPC) after focal cerebral ischemia and influence of lesion severity","volume":"372","author":"Weise","year":"2004","journal-title":"Neurosci. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0002-9440(10)63291-9","article-title":"Prion protein accumulation and neuroprotection in hypoxic brain damage","volume":"165","author":"McLennan","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.neuroscience.2005.06.095","article-title":"Female-specific neuroprotection against transient brain ischemia observed in mice devoid of prion protein is abolished by ectopic expression of prion protein-like protein","volume":"136","author":"Sakaguchi","year":"2005","journal-title":"Neuroscience"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zhang, B., Cowden, D., Zhang, F., Yuan, J., Siedlak, S., Abouelsaad, M., Zeng, L., Zhou, X., O\u2019Toole, J., and Das, A.S. (2015). Prion Protein Protects against Renal Ischemia\/Reperfusion Injury. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0141025"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/cvr\/cvu194","article-title":"The cellular prion protein counteracts cardiac oxidative stress","volume":"104","author":"Zanetti","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Chida, J., Hara, H., Yano, M., Uchiyama, K., Das, N.R., Takahashi, E., Miyata, H., Tomioka, Y., Ito, T., and Kido, H. (2018). Prion protein protects mice from lethal infection with influenza A viruses. PLoS Pathog., 14.","DOI":"10.1371\/journal.ppat.1007049"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1750-3639.2007.00061.x","article-title":"The role of the octarepeat region in neuroprotective function of the cellular prion protein","volume":"17","author":"Mitteregger","year":"2007","journal-title":"Brain Pathol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/37783","article-title":"The cellular prion protein binds copper in vivo","volume":"390","author":"Brown","year":"1997","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1042\/bj3440001","article-title":"Normal prion protein has an activity like that of superoxide dismutase","volume":"344","author":"Brown","year":"1999","journal-title":"Biochem. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1042\/BJ20051236","article-title":"Recombinant prion protein does not possess SOD-1 activity","volume":"392","author":"Jones","year":"2005","journal-title":"Biochem. J."},{"key":"ref_52","first-page":"1279","article-title":"No superoxide dismutase activity of cellular prion protein In vivo","volume":"384","author":"Hutter","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"39145","DOI":"10.1074\/jbc.C100443200","article-title":"Prion protein protects human neurons against Bax-mediated apoptosis","volume":"276","author":"Bounhar","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.mcn.2008.07.003","article-title":"The involvement of cellular prion protein in the autophagy pathway in neuronal cells","volume":"39","author":"Oh","year":"2008","journal-title":"Mol. Cell Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1518","DOI":"10.1242\/jcs.043604","article-title":"Dominant roles of the polybasic proline motif and copper in the PrP23\u201389-mediated stress protection response","volume":"122","author":"Haigh","year":"2009","journal-title":"J. Cell Sci."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Haigh, C.L., Tumpach, C., Drew, S.C., and Collins, S.J. (2015). The Prion Protein N1 and N2 Cleavage Fragments Bind to Phosphatidylserine and Phosphatidic Acid; Relevance to Stress-Protection Responses. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0134680"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/prot.22435","article-title":"Prion protein region 23\u201332 interacts with tubulin and inhibits microtubule assembly","volume":"77","author":"Osiecka","year":"2009","journal-title":"Proteins"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1042\/bj20020773","article-title":"Cell-surface prion protein interacts with glycosaminoglycans","volume":"368","author":"Pan","year":"2002","journal-title":"Biochem. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"18421","DOI":"10.1074\/jbc.M110406200","article-title":"Identification of the heparan sulfate binding sites in the cellular prion protein","volume":"277","author":"Warner","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.jmb.2009.10.075","article-title":"Structure of the flexible amino-terminal domain of prion protein bound to a sulfated glycan","volume":"395","author":"Taubner","year":"2010","journal-title":"J. Mol. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11062","DOI":"10.1073\/pnas.0609621104","article-title":"Cellular prion protein regulates beta-secretase cleavage of the Alzheimer\u2019s amyloid precursor protein","volume":"104","author":"Parkin","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1093\/nar\/gku1342","article-title":"The prion protein is critical for DNA repair and cell survival after genotoxic stress","volume":"43","author":"Bravard","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"8817","DOI":"10.1523\/JNEUROSCI.1103-12.2012","article-title":"The N-terminal, polybasic region of PrPC dictates the efficiency of prion propagation by binding to PrPSc","volume":"32","author":"Turnbaugh","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.1007\/s00705-017-3295-3","article-title":"Effects of prion protein devoid of the N-terminal residues 25\u201350 on prion pathogenesis in mice","volume":"162","author":"Das","year":"2017","journal-title":"Arch. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1128\/JVI.02805-15","article-title":"Mutated but Not Deleted Ovine PrPC N-Terminal Polybasic Region Strongly Interferes with Prion Propagation in Transgenic Mice","volume":"90","author":"Khalife","year":"2016","journal-title":"J. Virol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1007\/s12035-019-01804-5","article-title":"The N-Terminal Polybasic Region of Prion Protein Is Crucial in Prion Pathogenesis Independently of the Octapeptide Repeat Region","volume":"57","author":"Das","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1001\/archneur.1993.00540110011002","article-title":"Genetic and infectious prion diseases","volume":"50","author":"Prusiner","year":"1993","journal-title":"Arch. Neurol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ana.410350504","article-title":"Human spongiform encephalopathy: The National Institutes of Health series of 300 cases of experimentally transmitted disease","volume":"35","author":"Brown","year":"1994","journal-title":"Ann. Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Yamaguchi, Y., Miyata, H., Uchiyama, K., Ootsuyama, A., Inubushi, S., Mori, T., Muramatsu, N., Katamine, S., and Sakaguchi, S. (2012). Biological and biochemical characterization of mice expressing prion protein devoid of the octapeptide repeat region after infection with prions. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0043540"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Hara, H., Miyata, H., Das, N.R., Chida, J., Yoshimochi, T., Uchiyama, K., Watanabe, H., Kondoh, G., Yokoyama, T., and Sakaguchi, S. (2017). Prion Protein Devoid of the Octapeptide Repeat Region Delays Bovine Spongiform Encephalopathy Pathogenesis in Mice. J. Virol., 92.","DOI":"10.1128\/JVI.01368-17"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/S0896-6273(00)80653-4","article-title":"Neurological illness in transgenic mice expressing a prion protein with an insertional mutation","volume":"21","author":"Chiesa","year":"1998","journal-title":"Neuron"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"5574","DOI":"10.1073\/pnas.97.10.5574","article-title":"Accumulation of protease-resistant prion protein (PrP) and apoptosis of cerebellar granule cells in transgenic mice expressing a PrP insertional mutation","volume":"97","author":"Chiesa","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1111\/j.1471-4159.2008.05306.x","article-title":"Non-infectious aggregates of the prion protein react with several PrPSc-Directed antibodies","volume":"105","author":"Biasini","year":"2008","journal-title":"J. Neurochem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6237","DOI":"10.1016\/j.febslet.2005.09.099","article-title":"Transgenic mice expressing bovine PrP with a four extra repeat octapeptide insert mutation show a spontaneous, non-transmissible, neurodegenerative disease and an expedited course of BSE infection","volume":"579","author":"Castilla","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1523\/JNEUROSCI.3811-03.2004","article-title":"Different behavior toward bovine spongiform encephalopathy infection of bovine prion protein transgenic mice with one extra repeat octapeptide insert mutation","volume":"24","author":"Castilla","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Eigenbrod, S., Frick, P., Bertsch, U., Mitteregger-Kretzschmar, G., Mielke, J., Maringer, M., Piening, N., Hepp, A., Daude, N., and Windl, O. (2017). Substitutions of PrP N-terminal histidine residues modulate scrapie disease pathogenesis and incubation time in transgenic mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188989"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1126\/science.1980379","article-title":"Spontaneous neurodegeneration in transgenic mice with mutant prion protein","volume":"250","author":"Hsiao","year":"1990","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9126","DOI":"10.1073\/pnas.91.19.9126","article-title":"Serial transmission in rodents of neurodegeneration from transgenic mice expressing mutant prion protein","volume":"91","author":"Hsiao","year":"1994","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"10072","DOI":"10.1523\/JNEUROSCI.2542-09.2009","article-title":"A New Transgenic Mouse Model of Gerstmann-Str\u00e4ussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP","volume":"29","author":"Yang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1002\/j.1460-2075.1996.tb00467.x","article-title":"Prion protein (PrP) with amino-proximal deletions restoring susceptibility of PrP knockout mice to scrapie","volume":"15","author":"Fischer","year":"1996","journal-title":"EMBO J."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0896-6273(00)00046-5","article-title":"Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice","volume":"27","author":"Flechsig","year":"2000","journal-title":"Neuron"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/bmb\/66.1.43","article-title":"PrP knock-out and PrP transgenic mice in prion research","volume":"66","author":"Weissmann","year":"2003","journal-title":"Br. Med. Bull."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"10962","DOI":"10.1073\/pnas.90.23.10962","article-title":"Conversion of \u03b1-helices into \u03b2-sheets features in the formation of the scrapie prion proteins","volume":"90","author":"Pan","year":"1993","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"16990","DOI":"10.1073\/pnas.0909006106","article-title":"Natural and synthetic prion structure from X-ray fiber diffraction","volume":"106","author":"Wille","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Vazquez-Fernandez, E., Vos, M.R., Afanasyev, P., Cebey, L., Sevillano, A.M., Vidal, E., Rosa, I., Renault, L., Ramos, A., and Peters, P.J. (2016). The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathog., 12.","DOI":"10.1371\/journal.ppat.1005835"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1080\/19336896.2019.1569450","article-title":"The prion 2018 round tables (I): The structure of PrPSc","volume":"13","author":"Baskakov","year":"2019","journal-title":"Prion"},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Spagnolli, G., Rigoli, M., Orioli, S., Sevillano, A.M., Faccioli, P., Wille, H., Biasini, E., and Requena, J.R. (2019). Full atomistic model of prion structure and conversion. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007864"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"6597","DOI":"10.1128\/jvi.65.12.6597-6603.1991","article-title":"N-terminal truncation of the scrapie-associated form of PrP by lysosomal protease(s): Implications regarding the site of conversion of PrP to the protease-resistant state","volume":"65","author":"Caughey","year":"1991","journal-title":"J. Virol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"16188","DOI":"10.1016\/S0021-9258(18)41985-0","article-title":"Evidence for synthesis of scrapie prion proteins in the endocytic pathway","volume":"267","author":"Borchelt","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"37241","DOI":"10.1074\/jbc.M302036200","article-title":"The N-terminal region of the prion protein ectodomain contains a lipid raft targeting determinant","volume":"278","author":"Walmsley","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1042\/BJ20061592","article-title":"Aggregation of prion protein with insertion mutations is proportional to the number of inserts","volume":"403","author":"Yu","year":"2007","journal-title":"Biochem. J."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"38533","DOI":"10.1074\/jbc.M111.265645","article-title":"Copper alters aggregation behavior of prion protein and induces novel interactions between its N- and C-terminal regions","volume":"286","author":"Thakur","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Giachin, G., Mai, P.T., Tran, T.H., Salzano, G., Benetti, F., Migliorati, V., Arcovito, A., Della Longa, S., Mancini, G., and D\u2019Angelo, P. (2015). The non-octarepeat copper binding site of the prion protein is a key regulator of prion conversion. Sci. Rep., 5.","DOI":"10.1038\/srep15253"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1126\/science.279.5352.827","article-title":"A transmembrane form of the prion protein in neurodegenerative disease","volume":"279","author":"Hegde","year":"1998","journal-title":"Science"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/45574","article-title":"Transmissible and genetic prion diseases share a common pathway of neurodegeneration","volume":"402","author":"Hegde","year":"1999","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0092-8674(00)81572-X","article-title":"Expression of amino-terminally truncated PrP in the mouse leading to ataxia and specific cerebellar lesions","volume":"93","author":"Shmerling","year":"1998","journal-title":"Cell"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1038\/sj.emboj.7601507","article-title":"Neonatal lethality in transgenic mice expressing prion protein with a deletion of residues 105\u2013125","volume":"26","author":"Li","year":"2007","journal-title":"EMBO J."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"14005","DOI":"10.1523\/JNEUROSCI.1243-11.2011","article-title":"A nine amino acid domain is essential for mutant prion protein toxicity","volume":"31","author":"Westergard","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Turnbaugh, J.A., Westergard, L., Unterberger, U., Biasini, E., and Harris, D.A. (2011). The N-terminal, polybasic region is critical for prion protein neuroprotective activity. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025675"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"14724","DOI":"10.1074\/jbc.M110.214973","article-title":"An N-terminal polybasic domain and cell surface localization are required for mutant prion protein toxicity","volume":"286","author":"Solomon","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Wu, B., McDonald, A.J., Markham, K., Rich, C.B., McHugh, K.P., Tatzelt, J., Colby, D.W., Millhauser, G.L., and Harris, D.A. (2017). The N-terminus of the prion protein is a toxic effector regulated by the C-terminus. Elife, 6.","DOI":"10.7554\/eLife.23473"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:04:18Z","timestamp":1760177058000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/17\/6233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,28]]},"references-count":101,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["ijms21176233"],"URL":"https:\/\/doi.org\/10.3390\/ijms21176233","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,28]]}}}