Human prions

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

Keohane C. The human prion diseases. A review with special emphasis on new variant CJD and comments on surveillance. Clin Exp Pathol 1999 47 125-132. 

Human prion disease most commonly presents with a sporadic etiology 793... 

Acquired human prion diseases include kuru and variant CJD 794 Prion protein polymorphism contributes genetic susceptibility to prion disease 794... 

Distinct PrPSc types are seen in human prion disease 799... 

The prion diseases are a closely related group of neuro-degenerative conditions which affect both humans and animals. They have previously been described as the subacute spongiform encephalopathies, slow virus diseases and transmissible dementias, and include scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and the human prion diseases, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and kuru. Prion diseases are... 

Human prion diseases encompass the three etiological types of prion disease inherited, sporadic and acquired forms. 

Acquired human prion diseases include kuru and variant... 

Jackson, G. S. et al. Reversible conversion of monomeric human prion protein between native and fibrilogenic conformations. Science 283 1935-1937,1999. 

Asante, E. A. et al. BSE prions propagate as either variant CJD-like or sporadic CJD-like prion strains in transgenic mice expressing human prion protein. EMBO J. 21 6358-6366,2002. 

Fig. 2. Primary structure of hamster PrP (Stahl et al., 1993). The first 22 residues at the N-terminus are the signal sequence. PrPc is completely digested by proteinase K, whereas the N-terminal sequence of PrPSc to residue 89 (arrow, closed head) is digested. — CHO indicates the glycosylation sites at residues 181 and 197 Gpi the glycosylpho-sphatidylinositol anchor at 231 and the N-terminal octarepeats. In one case of human prion disease, a stop codon was found at 145 (arrow, open head) (Kitamoto et al., 1993). HI, H2, H3, and H4 denote the predicted a-helices (Huang et al, 1994, 1996), and A-C denote the a-helices and SI, S2 the /(-strands determined by solution NMR (James et al, 1997).

Fig. 3. Classification of human prion diseases. Sporadic the transformation from PrPc (circle) to PrPSc (square) occurs without apparent cause. Familial a point mutation ( ) is thought to facilitate the transformation. Infectious the transformation arises via PrPSc which acts as a template. The kinetic equations are defined by Eigen (1996). The infectious form includes kuru, iatrogenic CJD (iCJD), variant CJD (vCJD first reported in 1996), bovine spongiform encephalopathy (BSE first reported in 1985), and scrapie. In the nucleation-dependent model, monomeric PrPc and PrPSc are in chemical equilibrium.

NMR characterization of the recombinant mouse,hamster, bovine and human prion proteins showed that all these molecules share a common architecture, consisting of a flexible unstructured N-terminal tail of about 100 residues from position 23 to position 124 attached to a globular domain within residues 125-228. The globular domain contains a double-stranded anti-parallel /1-sheet and three ot-helices (Fig. 6). 

Monoclonal antibodies 3F4 (Senetk, St. Louis, MO) and F89/160.1.5 are used for immunostaining of prion protein. The monoclonal antibody 3F4 was developed by Kascsack et al. (1987) and shows immunoreactivity with the epitope around AA 112 of the human prion protein. The monoclonal antibody F89/160.1.5 was developed at the U.S. Department of Agriculture against a synthetic peptide representing residues 146-159 of... 

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

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