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Most of these histopathological phenotypes (histotypes) co-distribute with distinct pairings of methionine (M)\/valine (V) genotypes at codon 129 of the prion protein (PrP) gene and the type (1 or 2) of the disease-associated PrP (PrP<jats:sup>D<\/jats:sup>). Types 1 and 2 are defined by the molecular mass (~\u200921\u00a0kDa and\u2009~\u200919\u00a0kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrP<jats:sup>D<\/jats:sup> (resPrP<jats:sup>D<\/jats:sup>). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrP<jats:sup>D<\/jats:sup> type 1, T1) shows an electrophoretic profile where the resPrP<jats:sup>D<\/jats:sup> unglycosylated isoform is characterized by either one of two single bands of\u2009~\u200920\u00a0kDa (T1<jats:sup>20<\/jats:sup>) and\u2009~\u200921\u00a0kDa (T1<jats:sup>21<\/jats:sup>), or a doublet of\u2009~\u200921\u201320\u00a0kDa (T1<jats:sup>21\u221220<\/jats:sup>). We also showed that T1<jats:sup>20<\/jats:sup> and T1<jats:sup>21<\/jats:sup> in sCJDVV have different conformational features but are associated with indistinguishable histotypes. The presence of three distinct molecular profiles of T1 is unique and raises the issue as to whether T1<jats:sup>20<\/jats:sup> and T1<jats:sup>21<\/jats:sup> represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrP<jats:sup>D<\/jats:sup> profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T1<jats:sup>20<\/jats:sup> and T1<jats:sup>21<\/jats:sup> were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T1<jats:sup>21\u221220<\/jats:sup> resembled those of mice inoculated with T1<jats:sup>21<\/jats:sup> and T1<jats:sup>20<\/jats:sup>, respectively. As in sCJDVV1, Tg129V mice challenged with T1<jats:sup>21<\/jats:sup> and T1<jats:sup>20<\/jats:sup> generated virtually undistinguishable histotypes. In Tg129M mice, T1<jats:sup>21<\/jats:sup> was not replicated while T1<jats:sup>20<\/jats:sup> and T1<jats:sup>21\u221220<\/jats:sup> generated a\u2009~\u200921\u201320 \u00a0kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T1<jats:sup>20<\/jats:sup> and T1<jats:sup>21\u221220<\/jats:sup> challenged mice. Combined, these data indicate that T1<jats:sup>21<\/jats:sup> and T1<jats:sup>20<\/jats:sup> resPrP<jats:sup>D<\/jats:sup> represent distinct human prion strains associated with partially overlapping histotypes.<\/jats:p>","DOI":"10.1186\/s40478-021-01132-7","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T21:02:54Z","timestamp":1616706174000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Two distinct conformers of PrPD type 1 of sporadic Creutzfeldt\u2013Jakob disease with codon 129VV genotype faithfully propagate in vivo"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5770-3848","authenticated-orcid":false,"given":"Ignazio","family":"Cali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Carlos","family":"Espinosa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satish K.","family":"Nemani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alba","family":"Marin-Moreno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel V.","family":"Camacho","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rabail","family":"Aslam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuyuki","family":"Kitamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brian S.","family":"Appleby","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Maria","family":"Torres","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pierluigi","family":"Gambetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"key":"1132_CR1","doi-asserted-by":"publisher","first-page":"43295","DOI":"10.1038\/srep43295","volume":"7","author":"P Aguilar-Calvo","year":"2017","unstructured":"Aguilar-Calvo P, Xiao X, Bett C, Era\u00f1a H, Soldau K, Castilla J, Nilsson KPR, Surewicz WK, Sigurdson CJ (2017) Post-translational modifications in PrP expand the conformational diversity of prions in vivo. 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