Serum macroglobulin induces prion protein transition

The accumulation of the protease-resistant (PrPRes) abnormal form of the cellular prion protein (PrPC) plays a central role in Transmissible Spongiform Encephalopathies. In this report we describe a blood serum protein, which is precipitated by 9% PEG-6000, migrates in a sucrose gradient with a density of 1.21-1.17 g/ml, has a molecular mass of approximately 720 kDa and amino acid sequence as alpha(2)-Macroglobulin (alpha(2)-M). This protein can potentiate the conversion of the human recombinant prion protein (23-231 AA) as well as PrPC from the brain of mouse, hamster or cow from the sensitive to the resistant form. Under physiological conditions (pH 7.5; 0.15 M NaCl; 37 degrees C for 30 min; a nanomolar concentration range of PrP) the small, highly structured RNA (shs RNA) may activate the conversion process. We describe the design of an assay for screening for the biomolecules that prevent the PrP transition. Based on our experimental data we discuss the role of the alpha-helix to beta-sheet conformational change in the PrPSen to PrPRes conversion as well as the role of the alpha(2)-M during the initial stage of amyloidogenesis as well as the shs RNAs involvement in the formation of amyloid aggregates in neurodegenerative diseases.