{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T20:57:51Z","timestamp":1780606671487,"version":"3.54.1"},"reference-count":79,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T00:00:00Z","timestamp":1637193600000},"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":["21K07462"],"award-info":[{"award-number":["21K07462"]}],"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":["19H03548"],"award-info":[{"award-number":["19H03548"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008373","name":"Takeda (Japan)","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006679","name":"Kobayashi Magobe Memorial Medical Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/501100006679","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Waksman Foundation of Japan","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Conformational conversion of the cellular isoform of prion protein, PrPC, into the abnormally folded, amyloidogenic isoform, PrPSc, is an underlying pathogenic mechanism in prion diseases. The diseases manifest as sporadic, hereditary, and acquired disorders. Etiological mechanisms driving the conversion of PrPC into PrPSc are unknown in sporadic prion diseases, while prion infection and specific mutations in the PrP gene are known to cause the conversion of PrPC into PrPSc in acquired and hereditary prion diseases, respectively. We recently reported that a neurotropic strain of influenza A virus (IAV) induced the conversion of PrPC into PrPSc as well as formation of infectious prions in mouse neuroblastoma cells after infection, suggesting the causative role of the neuronal infection of IAV in sporadic prion diseases. Here, we discuss the conversion mechanism of PrPC into PrPSc in different types of prion diseases, by presenting our findings of the IAV infection-induced conversion of PrPC into PrPSc and by reviewing the so far reported transgenic animal models of hereditary prion diseases and the reverse genetic studies, which have revealed the structure-function relationship for PrPC to convert into PrPSc after prion infection.<\/jats:p>","DOI":"10.3390\/ijms222212439","type":"journal-article","created":{"date-parts":[[2021,11,18]],"date-time":"2021-11-18T08:53:56Z","timestamp":1637225636000},"page":"12439","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Virus Infection, Genetic Mutations, and Prion Infection in Prion Protein Conversion"],"prefix":"10.3390","volume":"22","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":[[2021,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"Prusiner","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_2","first-page":"785","article-title":"Etiology and pathogenesis of prion diseases","volume":"146","author":"DeArmond","year":"1995","journal-title":"Am. J. 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","first-page":"395","DOI":"10.1016\/j.tracli.2013.02.029","article-title":"The French surveillance network of Creutzfeldt-Jakob disease. Epidemiological data in France and worldwide","volume":"20","author":"Brandel","year":"2013","journal-title":"Transfus. Clin. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1093\/brain\/awm063","article-title":"Creutzfeldt-Jakob disease in Germany: A prospective 12-year surveillance","volume":"130","author":"Heinemann","year":"2007","journal-title":"Brain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e153","DOI":"10.1212\/WNL.0000000000008680","article-title":"Prion disease incidence in the United States: 2003\u20132015","volume":"94","author":"Maddox","year":"2020","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e2","DOI":"10.1016\/S1473-3099(19)30615-2","article-title":"Creutzfeldt-Jakob disease: A systematic review of global incidence, prevalence, infectivity, and incubation","volume":"20","author":"Uttley","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2632","DOI":"10.1093\/brain\/awn202","article-title":"Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series","volume":"131","author":"Webb","year":"2008","journal-title":"Brain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1016\/B978-0-444-63945-5.00015-5","article-title":"Fatal familial insomnia and sporadic fatal insomnia","volume":"153","author":"Cracco","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/S0140-6736(96)91412-9","article-title":"A new variant of Creutzfeldt-Jakob disease in the UK","volume":"347","author":"Will","year":"1996","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/bmb\/66.1.255","article-title":"Acquired prion disease: Iatrogenic CJD, variant CJD, kuru","volume":"66","author":"Will","year":"2003","journal-title":"Br. Med. Bull."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1136\/vr.121.18.419","article-title":"A novel progressive spongiform encephalopathy in cattle","volume":"121","author":"Wells","year":"1987","journal-title":"Vet. Rec."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Orge, L., Lima, C., Machado, C., Tavares, P., Mendonca, P., Carvalho, P., Silva, J., Pinto, M.L., Bastos, E., and Pereira, J.C. (2021). Neuropathology of Animal Prion Diseases. Biomolecules, 11.","DOI":"10.3390\/biom11030466"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"465","DOI":"10.7589\/0090-3558-18.4.465","article-title":"Spongiform encephalopathy of Rocky Mountain elk","volume":"18","author":"Williams","year":"1982","journal-title":"J. Wildl. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1624","DOI":"10.1099\/vir.0.042507-0","article-title":"Chronic wasting disease and atypical forms of bovine spongiform encephalopathy and scrapie are not transmissible to mice expressing wild-type levels of human prion protein","volume":"93","author":"Wilson","year":"2012","journal-title":"J. Gen. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"977","DOI":"10.3201\/eid1006.031082","article-title":"Chronic wasting disease and potential transmission to humans","volume":"10","author":"Belay","year":"2004","journal-title":"Emerg. Infect. Dis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1001\/archneur.58.10.1673","article-title":"Creutzfeldt-Jakob disease in unusually young patients who consumed venison","volume":"58","author":"Belay","year":"2001","journal-title":"Arch. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1212\/WNL.37.6.895","article-title":"The epidemiology of Creutzfeldt-Jakob disease: Conclusion of a 15-year investigation in France and review of the world literature","volume":"37","author":"Brown","year":"1987","journal-title":"Neurology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/S0140-6736(97)09468-3","article-title":"Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease (CJD)","volume":"351","author":"Masullo","year":"1998","journal-title":"Lancet"},{"key":"ref_20","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_21","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_22","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_23","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_24","doi-asserted-by":"crossref","first-page":"10109","DOI":"10.1038\/s41598-021-89586-6","article-title":"Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells","volume":"11","author":"Hara","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/0092-8674(85)90333-2","article-title":"A cellular gene encodes scrapie PrP 27-30 protein","volume":"40","author":"Oesch","year":"1985","journal-title":"Cell"},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"e3216","DOI":"10.1002\/psc.3216","article-title":"Prion protein-Semisynthetic prion protein (PrP) variants with posttranslational modifications","volume":"25","author":"Hackl","year":"2019","journal-title":"J. Pept. Sci."},{"key":"ref_28","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_29","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_30","doi-asserted-by":"crossref","unstructured":"Chida, J., Hara, H., Uchiyama, K., Takahashi, E., Miyata, H., Kosako, H., Tomioka, Y., Ito, T., Horiuchi, H., and Matsuda, H. (2020). Prion protein signaling induces M2 macrophage polarization and protects from lethal influenza infection in mice. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008823"},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/0092-8674(83)90168-X","article-title":"Scrapie prions aggregate to form amyloid-like birefringent rods","volume":"35","author":"Prusiner","year":"1983","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10962","DOI":"10.1073\/pnas.90.23.10962","article-title":"Conversion of alpha-helices into beta-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_34","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1038\/370471a0","article-title":"Cell-free formation of protease-resistant prion protein","volume":"370","author":"Kocisko","year":"1994","journal-title":"Nature"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1038\/35081095","article-title":"Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding","volume":"411","author":"Saborio","year":"2001","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.cell.2005.02.011","article-title":"In vitro generation of infectious scrapie prions","volume":"121","author":"Castilla","year":"2005","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1126\/science.1100195","article-title":"Synthetic mammalian prions","volume":"305","author":"Legname","year":"2004","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1126\/science.1183748","article-title":"Generating a prion with bacterially expressed recombinant prion protein","volume":"327","author":"Wang","year":"2010","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00401-017-1782-y","article-title":"Cofactors influence the biological properties of infectious recombinant prions","volume":"135","author":"Erana","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_40","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_41","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1126\/science.6815801","article-title":"Identification of a protein that purifies with the scrapie prion","volume":"218","author":"Bolton","year":"1982","journal-title":"Science"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/0092-8674(93)90635-4","article-title":"Seeding \u201cone-dimensional crystallization\u201d of amyloid: A pathogenic mechanism in Alzheimer\u2019s disease and scrapie?","volume":"73","author":"Jarrett","year":"1993","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/nature03989","article-title":"The most infectious prion protein particles","volume":"437","author":"Silveira","year":"2005","journal-title":"Nature"},{"key":"ref_44","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_45","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_46","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_47","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_48","doi-asserted-by":"crossref","first-page":"24129","DOI":"10.1074\/jbc.M114.578344","article-title":"Parallel in-register intermolecular beta-sheet architectures for prion-seeded prion protein (PrP) amyloids","volume":"289","author":"Groveman","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3389\/fmicb.2018.00559","article-title":"Structural and Functional Motifs in Influenza Virus RNAs","volume":"9","author":"Ferhadian","year":"2018","journal-title":"Front. Microbiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0022-2836(03)00919-7","article-title":"Small, highly structured RNAs participate in the conversion of human recombinant PrPSen to PrPRes in vitro","volume":"332","author":"Adler","year":"2003","journal-title":"J. Mol. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/nature01979","article-title":"RNA molecules stimulate prion protein conversion","volume":"425","author":"Deleault","year":"2003","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1159\/000149663","article-title":"Acceleration of scrapie disease in mice by an adenovirus","volume":"25","author":"Ehresmann","year":"1986","journal-title":"Intervirology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9839","DOI":"10.1128\/JVI.01137-08","article-title":"Small-ruminant lentivirus enhances PrPSc accumulation in cultured sheep microglial cells","volume":"82","author":"Stanton","year":"2008","journal-title":"J. Virol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1001\/archneur.65.6.762","article-title":"Induced neuroprotection independently from PrPSc accumulation in a mouse model for prion disease treated with simvastatin","volume":"65","author":"Haviv","year":"2008","journal-title":"Arch. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2674","DOI":"10.1038\/sj.emboj.7601162","article-title":"Retrovirus infection strongly enhances scrapie infectivity release in cell culture","volume":"25","author":"Leblanc","year":"2006","journal-title":"EMBO J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"a02715","DOI":"10.1101\/cshperspect.a027151","article-title":"Experimental Models of Inherited PrP Prion Diseases","volume":"7","author":"Watts","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_57","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_58","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_59","doi-asserted-by":"crossref","first-page":"10072","DOI":"10.1523\/JNEUROSCI.2542-09.2009","article-title":"A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP","volume":"29","author":"Yang","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_60","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_61","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_62","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_63","doi-asserted-by":"crossref","unstructured":"Friedman-Levi, Y., Meiner, Z., Canello, T., Frid, K., Kovacs, G.G., Budka, H., Avrahami, D., and Gabizon, R. (2011). Fatal prion disease in a mouse model of genetic E200K Creutzfeldt-Jakob disease. PLoS Pathog., 7.","DOI":"10.1371\/journal.ppat.1002350"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1099\/vir.0.007930-0","article-title":"Absence of spontaneous disease and comparative prion susceptibility of transgenic mice expressing mutant human prion proteins","volume":"90","author":"Asante","year":"2009","journal-title":"J. Gen. Virol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"14759","DOI":"10.1073\/pnas.1312006110","article-title":"Profoundly different prion diseases in knock-in mice carrying single PrP codon substitutions associated with human diseases","volume":"110","author":"Jackson","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.neuron.2008.09.008","article-title":"Mutant prion protein expression causes motor and memory deficits and abnormal sleep patterns in a transgenic mouse model","volume":"60","author":"Dossena","year":"2008","journal-title":"Neuron"},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Bouybayoune, I., Mantovani, S., Del Gallo, F., Bertani, I., Restelli, E., Comerio, L., Tapella, L., Baracchi, F., Fernandez-Borges, N., and Mangieri, M. (2015). Transgenic fatal familial insomnia mice indicate prion infectivity-independent mechanisms of pathogenesis and phenotypic expression of disease. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004796"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.neuron.2009.07.026","article-title":"Spontaneous generation of prion infectivity in fatal familial insomnia knockin mice","volume":"63","author":"Jackson","year":"2009","journal-title":"Neuron"},{"key":"ref_69","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_70","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_71","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_72","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_73","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_74","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. (2018). 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_75","doi-asserted-by":"crossref","unstructured":"Uchiyama, K., Miyata, H., Yamaguchi, Y., Imamura, M., Okazaki, M., Pasiana, A.D., Chida, J., Hara, H., Atarashi, R., and Watanabe, H. (2020). Strain-Dependent Prion Infection in Mice Expressing Prion Protein with Deletion of Central Residues 91\u2013106. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197260"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"5626","DOI":"10.1128\/JVI.06606-11","article-title":"Mouse prion protein (PrP) segment 100 to 104 regulates conversion of PrPC to PrPSc in prion-infected neuroblastoma cells","volume":"86","author":"Hara","year":"2012","journal-title":"J. Virol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/jb\/mvs148","article-title":"Species-barrier phenomenon in prion transmissibility from a viewpoint of protein science","volume":"153","author":"Hagiwara","year":"2013","journal-title":"J. Biochem."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"8342","DOI":"10.1073\/pnas.0402254101","article-title":"Evidence for assembly of prions with left-handed beta-helices into trimers","volume":"101","author":"Govaerts","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4540","DOI":"10.1016\/j.molcel.2021.08.011","article-title":"High-resolution structure and strain comparison of infectious mammalian prions","volume":"81","author":"Kraus","year":"2021","journal-title":"Mol. Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12439\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:32:09Z","timestamp":1760167929000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/22\/12439"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,18]]},"references-count":79,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["ijms222212439"],"URL":"https:\/\/doi.org\/10.3390\/ijms222212439","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,18]]}}}