Characterization of neurodegeneration in transgenic mice expressing mutant prion proteins

Transgenic mice overexpressing the equivalent of Gerstmann-Straussler-Scheinker syndrome linked P102L mutation, referred to as Tg(GSS-Leu), developed clinical and neuropathological features of prion disease but failed to produce protease-resistant PrPSc in their brains (Hsiao et al, 1990; Hsiao et al., 1994; Telling et al., 1996). To explore the dissociation of apparent prion disease development and accumulation of protease-resistant PrP Sc we created another series of Tg mice expressing the MoPrP-P101L mutation as well as various artificial point mutations at codon 101. We discovered that overexpression of the natural MoPrP-P101L, and artificial MoPrP-P101I and MoPrP-P101Y transgenes resulted in spontaneous neurodegenerative disease suggesting that the transgenes containing artificial point mutations also misfolded into neurotoxic molecules. While the brains of clinically sick Tg(GSS) and Tg(GSS-Ile) accumulated disease-associated mutant MoPrP that was reactive with scrapie-specific monoclonal antibody 15133 (Korth et al., 1997) and a disease-specific "cold-PK" resistant ∼22-24 kDa fragment precipitated by phosphotungstic acid (Tremblay et al., 2004), Tg(GSS-Tyr) brain lacked these molecular correlates of disease. The failure to transmit disease from the brains of sick Tg(GSS), Tg (GSS-Ile) and Tg(GSS-Tyr) mice to wild type mice or Tg mice expressing wild type levels of the mutant transgene indicated that the brains of spontaneously sick mice lacked bona fide prion infectivity, however, inoculation into the brains of medium or high expressing Tg(GSS) mice resulted in accelerated disease indicating that the these disease-associated mutant proteins acquired a catalytic activity that lead to a protein misfolding cascade in the inoculated host. Using an accelerating rotarod, we have detected a sensorimotor impairment detected early in the presymptomatic state in Tg(GSS) mice that precedes development of overt CNS dysfunction and spongiform deterioration. We also found that Zurich I FVB/ Prnp0/0 mice consistently performed significantly worse on the rotarod task than wild type mice. This motor dysfunction corresponded to vacuolar degeneration in the cerebellum and basal ganglia which has never been described in Prnp0/0 mice and indicates a novel role for PrPC at positions in the brain that are responsible for maintenance of motor coordination and balance.