Prion strain diversity following passage of sCJD(MM1) and CWD prions in Tg(I109) mice.

<p>(<b>A</b>) Age-adjusted Kaplan-Meier survival curves for Tg(I109) mice inoculated with sCJD(MM1) prions (two independent cases) or sCJD(MM1) prions that were passaged in Tg(HuPrP) mice (green lines, <i>n</i> = 6–7 each); CWD prions (blue line, <i>n</i> = 7); Sc237 prions (orange line, <i>n</i> = 7); or RML prions (red line, <i>n</i> = 8). There was substantial overlap between the appearance of spontaneous signs of neurologic illness in uninoculated Tg(I109) mice (black line, <i>n</i> = 13) and the survival of Tg(I109) mice inoculated with CWD and sCJD(MM1) prions. For all inoculation experiments, the mice were inoculated at ∼60 days of age. (<b>B</b>–<b>H</b>) Analysis of PK-resistant PrP^Sc in the brains of Tg(I109) mice inoculated with sCJD(MM1) (<b>C</b>, <b>D</b>); sCJD(MM1) prions that were passaged in Tg(HuPrP) mice (<b>E</b>); CWD (<b>F</b>); Sc237 (<b>G</b>); and RML prions (<b>H</b>). With the exception of one lane in panel B (−), all samples were digested with PK. All inoculation experiments resulted in the generation of PK-resistant PrP^Sc. Brain homogenate from an uninoculated, 171-d-old asymptomatic Tg(I109) mouse (None) is shown as a control. In panels C–H, each lane represents the PK-resistant PrP^Sc in the brain of an individual animal within the experiment. For each prion isolate, PK-resistant PrP^Sc in the brain of an infected Tg(M109) mouse is shown for comparison. Whereas inoculation of Tg(I109) mice with RML or Sc237 prions resulted in PK-resistant PrP^Sc conformers with the same electrophoretic mobility as those present in Tg(M109) mice (black arrows), inoculation with CWD or sCJD(MM1) isolates resulted in the emergence of novel PK-resistant PrP^Sc conformers with different electrophoretic mobilities (red arrows) in some animals. For all immunoblots, loading quantities were adjusted prior to immunoblotting to give similar signal intensities across all samples. Lowercase letters below blots identify samples referred to in the main text. In panels B–H, molecular weight measurements are shown in kDa. PrP was detected using the antibody HuM-P.