Besides oxidative mechanisms, an atypical inflammatory response is activated in the central nervous system of prion-infected individuals, and consequently a number of (pro inflammatory mediators are deregulated in the CSF of patients with prion diseases (Table 1) [ 40].
This type of astrocytic response is observed in all our model systems of transmissible prion disease, but is absent from the nontransmissible forms of PrP (i.e., amyloid plaques in absence of clinical disease), suggesting that this single mouse may represent a transmission of infection rather than a consequence of seeding of inoculum (25, 28 ).
These factors point again to a major involvement of the innate immune system in the pathogenesis of prion disease, and furthermore suggest the existence of new targets for possible therapeutic intervention.
Although, the central nervous system is the principal site of prion accumulation and replication, and the only site where prion-related tissue damage is seen, PrPSc and prion infectivity can be found in peripheral compartments such as spleen and muscle.
PrPSc aggregates accumulate predominantly in the central nervous system (CNS), and definitive diagnosis of prion diseases currently relies on the post mortem detection of PrPSc in CNS tissue by immunohistochemistry, Western blotting, or ELISA [ 10].
In addition to macrophages and follicular dendritic cells, prion containing cells consistent with afferent lymph dendritic cells were identified and are suggested as a likely vehicle for carriage of prions from initial site of uptake to the lymphoreticular system, and as potential carriers of prion protein in blood.
This observation raises the possibility that intercurrent disease, or even vaccination, which will affect the state of activation of the lymphoid system, might influence the dynamics of prion accumulation; it remains to be determined whether this may lead to any effect on susceptibility to infection or progression of the disease.
Little is known about the molecular processes that occur in the lymphoreticular system in early and late stages of prion disease.
In our system, the prion domain of Ure2 provides a naturally stable linker between the fibril core and enzymatic domain and allows the immobilization of the enzymes with high efficiency and homogeneity.
It is characterized by accumulation in the central nervous system of a pathological agent, the prion protein (PrPSc) [ 1], which differs from the endogenous normal form (PrPc) in conformational changes, partial resistance to proteolytic degradation and insolubility in the presence of detergents [ 2, 3].
