Transmission characteristics of heterozygous cases of Creutzfeldt-Jakob disease with variable abnormal prion protein allotypes

Abstract

In the human prion disease Creutzfeldt-Jakob disease (CJD), different CJD neuropathological subtypes are defined by the presence in normal prion protein (PrP C) of a methionine or valine at residue 129, by the molecular mass of the infectious prion protein PrP Sc , by the pattern of PrP Sc deposition, and by the distribution of spongiform change in the brain. Heterozygous cases of CJD potentially add another layer of complexity to defining CJD subtypes since PrP Sc can have either a methionine (PrP Sc-M129) or valine (PrP Sc-V129) at residue 129. We have recently demonstrated that the relative amount of PrP Sc-M129 versus PrP Sc-V129, i.e. the PrP Sc allotype ratio, varies between heterozygous CJD cases. In order to determine if differences in PrP Sc allotype correlated with different disease phenotypes, we have inoculated 10 cases of heterozygous CJD (7 sporadic and 3 iatrogenic) into two transgenic mouse lines overexpressing PrP C with a methionine at codon 129. In one case, brain-region specific differences in PrP Sc allotype appeared to correlate with differences in prion disease transmission and phenotype. In the other 9 cases inoculated, the presence of PrP Sc-V129 was associated with plaque formation but differences in PrP Sc allotype did not consistently correlate with disease incubation time or neuropathology. Thus, while the PrP Sc allotype ratio may contribute to diverse prion phenotypes within a single brain, it does not appear to be a primary determinative factor of disease phenotype.

Lack of the immune adaptor molecule SARM1 accelerates disease in prion infected mice and is associated with increased mitochondrial respiration and decreased expression of NRF2

“…Processing of brains from RML and NBH inoculated mice for the detection of PrP Sc as well as SDS-PAGE, transfer of proteins to polyvinylidene difluoride (PVDF) membrane (Millipore, Burlington MA), and membrane development were all done as described previously [ 47 ]. For detection of proteins other than PrP Sc , digestion with proteinase K was omitted.…”

Sensitive detection of pathological seeds of α-synuclein, tau and prion protein on solid surfaces

“…We then tested sfRT-QuIC in a more clinically relevant scenario. We used surgical instruments (forceps and scissors) that had been used to cut brain tissue from sCJD-infected transgenic mice expressing only human PrP (Tg66) [ 46 ], dry wiped with gauze (n = 2) or not (n = 3), and then air-dried prior to the application of SM ( Fig 2C ). For three of the instruments, including a wiped scissor, SM dilutions of 10 −2 –10 −5 were positive in all quadruplicate wells, while SMs from the other two instruments were uniformly positive out to 10 −3 and 10 −4 dilutions ( Fig 7 ).…”

Sporadic Creutzfeldt–Jakob disease infected human cerebral organoids retain the original human brain subtype features following transmission to humanized transgenic mice

“…The incubation periods of different type 1 and 2 brain homogenates in humanized mice vary in the literature [ 23 , 33 – 35 ]. This is at least partially due to the mouse strain, which may have different PrP C expression levels, and classification system used to define the subtypes.…”

“…Tg66 transgenic mice overexpressing human PrP C were used for this study. These mice have been shown to be susceptible to prion disease by infection with MV1 and 2 sCJD prions, with distinct disease courses and biochemistry apparent with the different inocula [ 23 ]. Generation of these mice was described previously [ 22 ].…”