Conditional expression of PrP and its effect on transmissible spongiform encephalopathy

The expression of prion protein (PrP) has been proven to be essential for the development of transmissible spongiform encephalopathy (TSE). PrP knockout mice are completely resistant to TSE disease. We have developed and established a transgenic mouse model in which PrP expression can be controlled using the cre/lox system. Using this system we aim to determine in which cells and when PrP expression is vital to disease progression, both within the central nervous system (CNS) and also during neuroinvasion following peripheral challenge. Currently we are investigating the role of PrP expression in CNS neurones and peripheral myelinating glial cells (Schwann cells).

Removal of PrP expression from myelinating glial cells revealed no effect on TSE neuroinvasion. This result was surprising as ~ 90 % of the PrP was lost from peripheral nerves including all glycosylated PrP species. This model is being investigated further to determine the cellular contribution to PrP glycoprofile and also the possible involvement of PrP in myelination or axon-glial interaction.

Removal or PrP expression from neurones via a tamoxifen-inducible cre model revealed a ~ 50 % loss of PrP from whole brain. This is despite neurones only contributing to ~ 10 % of brain matter. Following intracerebral challenge we are currently observing a significant lengthening of incubation period, though these experiments are still in progress. Pathological examination of infected neuronal PrP knockout mice reveals much less PrPSc deposition and neuronal loss when compared to infected non-induced litter mates. These results indicate protection of neurones against disease effects.