{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T16:02:52Z","timestamp":1778860972113,"version":"3.51.4"},"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T00:00:00Z","timestamp":1666828800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Prion diseases are a group of rare, transmissible, and invariably fatal neurodegenerative diseases that affect both humans and animals. The cause of these diseases is misfolding of the prion protein into pathological isoforms called prions. Of all human prion diseases, 10\u201315% of cases are genetic and the E200K mutation, which causes familial Creutzfeldt-Jakob disease (CJD), is the most prevalent. For both sporadic and genetic disease, it remains uncertain as to how initial protein misfolding is triggered. Prior studies have linked protein misfolding with oxidative stress insults, deregulated interactions with cellular cofactors, and viral infections. Our previous work developed a cerebral organoid (CO) model using human induced pluripotent stem cells containing the E200K mutation. COs are three-dimensional human neural tissues that permit the study of host genetics and environmental factors that contribute to disease onset. Isogenically matched COs with and without the E200K mutation were used to investigate the propensity of E200K PrP to misfold following cellular insults associated with oxidative stress. Since viral infections have also been associated with oxidative stress and neurodegenerative diseases, we additionally investigated the influence of Herpes Simplex Type-1 virus (HSV1), a neurotropic virus that establishes life-long latent infection in its host, on E200K PrP misfolding. While COs proved to be highly infectable with HSV1, neither acute nor latent infection, or direct oxidative stress insult, resulted in evidence of E200K prion misfolding. We conclude that misfolding into seeding-active PrP species is not readily induced by oxidative stress or HSV1 in our organoid system.<\/jats:p>","DOI":"10.1371\/journal.pone.0277051","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T17:49:22Z","timestamp":1666892962000},"page":"e0277051","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["Stress and viral insults do not trigger E200K PrP conversion in human cerebral organoids"],"prefix":"10.1371","volume":"17","author":[{"given":"Anna","family":"Smith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5059-7672","authenticated-orcid":true,"given":"Bradley R.","family":"Groveman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clayton","family":"Winkler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan","family":"Walters","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jue","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenquan","family":"Zou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7450-6926","authenticated-orcid":true,"given":"Simote T.","family":"Foliaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7591-1149","authenticated-orcid":true,"given":"Cathryn L.","family":"Haigh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2022,10,27]]},"reference":[{"issue":"Suppl 1","key":"pone.0277051.ref001","doi-asserted-by":"crossref","first-page":"i36","DOI":"10.1136\/jnnp.2004.036137","article-title":"Prion diseases","volume":"75 Suppl 1","author":"RS Knight","year":"2004","journal-title":"J Neurol Neurosurg Psychiatry"},{"issue":"5","key":"pone.0277051.ref002","article-title":"Genetic PrP Prion Diseases","volume":"10","author":"MO Kim","year":"2018","journal-title":"Cold Spring Harb Perspect Biol."},{"issue":"23","key":"pone.0277051.ref003","doi-asserted-by":"crossref","first-page":"13363","DOI":"10.1073\/pnas.95.23.13363","article-title":"Prions","volume":"95","author":"SB Prusiner","year":"1998","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"322","key":"pone.0277051.ref004","doi-asserted-by":"crossref","first-page":"322ra9","DOI":"10.1126\/scitranslmed.aad5169","article-title":"Quantifying prion disease penetrance using large population control cohorts","volume":"8","author":"EV Minikel","year":"2016","journal-title":"Sci Transl Med."},{"issue":"4","key":"pone.0277051.ref005","doi-asserted-by":"crossref","first-page":"101770","DOI":"10.1016\/j.jbc.2022.101770","article-title":"Prion protein with a mutant N-terminal octarepeat region undergoes cobalamin-dependent assembly into high-molecular weight complexes","volume":"298","author":"N Daude","year":"2022","journal-title":"J Biol Chem"},{"issue":"3","key":"pone.0277051.ref006","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1016\/j.bbrc.2015.04.048","article-title":"Cavitation during the protein misfolding cyclic amplification (PMCA) method\u2014The trigger for de novo prion generation?","volume":"461","author":"CL Haigh","year":"2015","journal-title":"Biochem Biophys Res Commun"},{"key":"pone.0277051.ref007","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/bs.pmbts.2020.07.009","article-title":"Cofactor molecules: Essential partners for infectious prions","volume":"175","author":"S. 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