A novel anti-prion protein monoclonal antibody and its single-chain fragment variable derivative with ability to inhibit abnormal prion protein accumulation in cultured cells.

mAbs T1 and T2 were established by immunizing PrP gene ablated mice with recombinant MoPrP of residues 121-231. Both mAbs were cross-reactive with PrP from hamster, sheep, cattle and deer. A linear epitope of mAb T1 was identified at residues 137-143 of MoPrP and buried in PrP(C) expressed on the cell surface.

[Prion protein structure and its relationships with pathogenesis].

In order to explore the structural domains of prion protein (PrP) that are required for the isoform conversion, prion formation and neurodegenerative effects, we designed a series of PrP deletion mutants and studied, using prion-infected cultured cells and transgemic (Tg) mice, 1) if these mutants can be converted to the abnormal isoform, 2) constitute prions, and 3) cause neurodegeneration when converted and accumulated in mouse brains. We discovered that a mutant PrP with deletions at the N-terminus and the middle portion retained all the three abilities. The molecule named PrP106 was composed of 106 amino acids, nearly a half of 208 composing wild type PrP.

Humanized knock-in mice expressing chimeric prion protein showed varied susceptibility to different human prions.

Mice to which human prions efficiently transmit in short incubation periods are valuable not only as research tools of human prions but also as reliable diagnostic tools. We recently produced a line of knock-in mouse expressing a unique human-mouse chimeric PrP (Ki-ChM mouse), which has mouse-specific residues practically only at the C-terminal part after posttranslational modification, and here we attempted transmission of various human prions to assess the susceptibility profile of the mouse. Susceptibility varied considerably depending on prions inoculated: highly susceptible to MM1 and MV1 types of sporadic Creutzfeldt-Jakob disease (CJD), developing disease within approximately 150 days, familial CJD with M232R mutation, and dura graft-associated CJD (dCJD) without amyloid plaque; less susceptible to MM2-type sporadic CJD and variant CJD, with some mice lacking any sign of transmission; and totally resistant to VV2 type sporadic CJD and dCJD with amyloid plaque.

Association of an 11-12 kDa protease-resistant prion protein fragment with subtypes of dura graft-associated Creutzfeldt-Jakob disease and other prion diseases.

Creutzfeldt-Jakob disease can develop in subjects given a cadaveric dura mater graft (dCJD). This disease has a phenotypic heterogeneity despite the lack of genetic variation. Numerous plaque-type prion protein (PrP) deposits are found in the brain of some but not all subjects; hence, there may be two subtypes of this clinical entity.

Follicular dendritic cell of the knock-in mouse provides a new bioassay for human prions.

Infectious prion diseases initiate infection within lymphoid organs where prion infectivity accumulates during the early stages of peripheral infection. In a mouse-adapted prion infection, an abnormal isoform (PrP(Sc)) of prion protein (PrP) accumulates in follicular dendritic cells within lymphoid organs. Human prions, however, did not cause an accumulation of PrP(Sc) in the wild type mice.