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A characteristic trait of prion diseases is the structural modification of a host protein, the prion protein. Until now, only the structure of the normal protein had been determined experimentally, while that of the modified protein had only been suggested or modelled.

The joint efforts by INRA researchers and specialists in structural biology at the CNRS were based on an original approach. The image of the prion molecule was deduced from X-ray analyses of a crystal of a complex between this protein and a specific antibody fragment bound to it.

And, as shown by the Institut Pourquier (associated in the publication), this antibody, produced by INRA, has proved to be particularly effective in recognising both the normal form of different ovine prion protein variants and the pathological ovine form. This has made it possible to affirm that the region of the protein recognised by the antibody (or epitope) is conserved in the pathological form. The presence of this epitope also suggests that the structure of the two principal helixes of the protein is conserved.

The structural modification which is characteristic of the disease may thus only concern a very limited zone of the protein, to which therapeutic approaches could be targeted. In sheep, it is precisely this zone which concentrates the mutations influencing susceptibility to scrapie. It has been possible to generalise this result to several mammal species (including primates) which are naturally or experimentally sensitive to prion diseases; to date, no counterexamples have been identified.

Use of this antibody has made it possible to develop a new, rapid and easy-to-use test for the post mortem detection of prion diseases in the brains of slaughtered animals. This French test was born of a partnership between INRA and the Institut Pourquier. On November 17, 2004, it was validated for the detection of Bovine Spongiform Encephalitis by the EFSA (European Food Safety Agency) having passed through the double filter of evaluation in the laboratory and trials in the field (the latter involving analyses on 200 positive samples, 200 negative, autolysed or putrified samples from rendering and more than 10,000 negative samples from abattoirs). Validation certifies that the performance of this test is at least equivalent to that of those which have already been approved.

Two objectives have thus been achieved in tandem: an answer has been found to fundamental questions on the conformation dynamics of the prion protein, and thanks to the same tool, a diagnostic test has been developed for animal prion diseases.

Publication:

F.EGHIAIAN (2), J.GROSCLAUDE (1), S.LESCEU (3), P.DEBEY (4), B.DOUBLET (2), E.TREGUER (2), H.REZAEI (2) and M.KNOSSOW (2).
Insight into the PrPC/PrPSc conversion from the structures of antibody-bound ovine prion scrapie-susceptibility variants.

Proc.Natl.Acad.Sci.USA, 101, 10254-10259, 13 July 2004.

(1) Unité Virologie et Immunologie Moléculaires, INRA 78352 Jouy-en-Josas

(2) Laboratoire d’Enzymologie et de Biochimie Structurales, CNRS, 91198 Gif-sur-Yvette

(3) Institut Pourquier, 326 rue de la Galéra, 34097 Montpellier

(4) Muséum National d'Histoire Naturelle, 75005 Paris