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11,Pág. Centro de Investigación en Sanidad Animal (CISA), Current classifications of sporadic Creutzfeldt-Jakob disease (sCJD) identify five subtypes associated with different disease phenotypes. 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 (PrPD). Types 1 and 2 are defined by the molecular mass (~ 21 kDa and ~ 19 kDa, respectively) of the unglycosylated isoform of the proteinase K-resistant PrPD (resPrPD). We recently reported that the sCJDVV1 subtype (129VV homozygosity paired with PrPD type 1, T1) shows an electrophoretic profile where the resPrPD unglycosylated isoform is characterized by either one of two single bands of ~ 20 kDa (T120) and ~ 21 kDa (T121), or a doublet of ~ 21-20 kDa (T121-20). We also showed that T120 and T121 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 T120 and T121 represent distinct prion strains. To answer this question, brain homogenates from sCJDVV cases harboring each of the three resPrPD profiles, were inoculated to transgenic (Tg) mice expressing the human PrP-129M or PrP-129V genotypes. We found that T120 and T121 were faithfully replicated in Tg129V mice. Electrophoretic profile and incubation period of mice challenged with T121-20 resembled those of mice inoculated with T121 and T120, respectively. As in sCJDVV1, Tg129V mice challenged with T121 and T120 generated virtually undistinguishable histotypes. In Tg129M mice, T121 was not replicated while T120 and T121-20 generated a ~ 21-20 kDa doublet after lengthier incubation periods. On second passage, Tg129M mice incubation periods and regional PrP accumulation significantly differed in T120 and T121-20 challenged mice. Combined, these data indicate that T121 and T120 resPrPD represent distinct human prion strains associated with partially overlapping histotypes., This work was funded in part by the Alliance BioSecure Research Foundation [FABS FRM-2014 to J.M.T], Spanish Ministerio de Economía Industria y Competitividad [AGL2016-78054-R (AEI/FEDER, UE) to J.M.T. and J.C.E], Fundació La Marató de TV3 [201821-30-31-32 to J.C.E] and AMM was supported by Instituto Nacional de Investigación y Tecnología Agraria y Agroalimentaria [fellowship INIA-FPI-SGIT-2015–02]. This study was supported by National Institutes of Health Grants R01 NS083687 and the Charles S. Britton Fund. to P. Gambetti, by the National Institute of Allergy and Infectious Diseases P01 AI077774 grant to C. Soto, and by the K99/R00 AG068359 to I. Cali. As a trainee of the research education component (REC) of the Cleveland Alzheimer’s Disease Research Center (CADRC), the work of I. Cali was also supported by the NIA P30 AG062428 01. The National Prion Disease Pathology Surveillance Center is funded by CDC (NU38CK00048).