Over the last 30 years, many drugs have been tested both in cell culture and in vivo for their ability to prevent the generation of prions and the development of transmissible spongiform encephalopathies. Among the compounds tested, dendrimers are defined by their branched and repeating molecular structure. The anti-prion activity of new cationic phosphorus-containing dendrimers (P-dendrimers) with tertiary amine end-groups was tested. These molecules had a strong anti-prion activity, decreasing both PrP^Sc and infectivity in scrapie-infected cells at non-cytotoxic doses. They can bind PrP and decrease the amount of pre-existing PrP^Sc from several prion strains, including the BSE strain. More importantly, when tested in a murine scrapie model, the dendrimers were able to decrease PrP^Sc accumulation in the spleen by more than 80 %. These molecules have a high bio-availability and therefore exhibit relevant potential for prion therapeutics for at least post-exposure prophylaxis.

The use of anti‐PrP antibodies represents one of the most promising strategies for the treatment of prion diseases. In the present study, we screened various anti‐PrP antibodies with the aim of identifying those that would block PrP^Sc replication in prion‐infected cell culture. Two antibodies, SAF34 recognizing the flexible octarepeats region on HuPrP protein, and SAF61 directed against PrP amino acid residues (144–152), not only inhibited PrP^Sc formation in prion‐infected neuroblastoma cells but also decreased the PrP^C levels in non‐infected N2a cells. In addition, treatment with both SAF34 and SAF61 antibodies decreased PrP^C and PrP^Sc levels in the cells synergistically. In the presence of both antibodies, our results showed that the mode of action which leads to the disappearance of PrP^Sc in cells is directly coupled to PrP^C degradation by reducing the half‐life of the PrP^C protein.

Cell cultures represent relevant and useful experimental models of transmissible spongiform encephalopathies (TSEs). They are able to promote, upon subpassaging, stable and persistent replication of PrP^Sc as well as infectivity. To date, only a few cell culture models permissive to prion replication are available. Among them, mouse neuroblastoma cell lines (N2a) are most commonly used. While they correspond to homologous models supporting propagation of mouse-adapted scrapie strains, recent studies have reported heterologous models sensitive to natural occurring disease. Infected cell culture models have provided some valuable insights into the biogenesis of PrP^Sc in terms of conversion, subcellular localisations, physiopathological consequences and species-barrier determinants. They have also contributed to the screening and the study of possible therapeutic compounds and to the development of new strategies for the investigation of TSE-specific diagnostic markers.

Prion diseases are fatal transmissible neurodegenerative disorders characterized by the accumulation of an abnormally folded isoform of the cellular prion protein (PrP^C) denoted PrP^Sc. Recently, wild-type and pathogenic PrP mutants have been shown to be degraded by the endoplasmic reticulum-associated degradation proteasome pathway after translocation into the cytosol. We show here that a protease resistant form of PrP accumulated in the nuclei of prion-infected cells independently of proteasome activity, and that this nuclear translocation required an intact microtubule network. Moreover, our results show for the first time that nuclear PrP interacts with chromatin in vivo, which may have physiopathological consequences in prion diseases