Determination of the structure of the disease-associated, srapie form of the prion protein

Projektinformationen

PRION PROTEIN

ID Finanzhilfevereinbarung: 11636

Startdatum 1 Dezember 2004

Enddatum 30 November 2006

Finanziert unter

• Human resources and Mobility in the specific programme for research, technological development and demonstration "Structuring the European Research Area" under the Sixth Framework Programme 2002-2006

Gesamtkosten € 0,00

EU-Beitrag € 152 569,00

Koordiniert durch

BIOLOGICAL RESEARCH CENTER, HUNGARIAN ACADEMY OF SCIENCES
Hungary

Final Activity Report Summary - PRION PROTEIN (Determination of the structure of the disease-associated, srapie form of the prion protein)

Although the exact nature of the infectious agents, the prions, is not known, the presence of the abnormal form is a generally accepted indication for the on-going progression of the disease process. It constitutes the best surrogate marker so far. One of the major problems in developing a method based on the detection of the abnormal form is that very little structural information is available about the abnormal form which would facilitate the generation of monoclonal antibodies with high sensitivity. The difference between the two forms is conformational only, no alteration in the covalent structure of the forms has been revealed. The abnormal form has an elevated b-sheet content indicating a dramatic conformational change. It has a high tendency for aggregation and soluble only in detergents and denaturants. However, these treatments also destroy the structure of the abnormal form as indicated by the loss of the b-sheet content and most importantly, the loss of the infectivity in the sample. The most characteristic feature of the abnormal form is its elevated protease resistance and digestion pattern that is used most frequently for its identification.

Our purpose was here to gain more structural information about the abnormal form that would facilitate the development of a sensitive detection. We found regions in the N-terminal part of the protease-resistant core of the abnormal form that are exposed for antibody detection in accord with the literature. By contrast, the C-terminal long helixes that are depicted as exposed parts in the most recent models of the abnormal form were not available for antibody detection.

Using antibodies against the rather N-terminal part of the protease-resistant core of the protein, we managed to detect disease-associated forms of the protein in the blood plasma of TSE-affected hamsters.