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Title: A PRION PROTEIN EPITOPE SELECTIVE FOR THE PATHOLOGICALLY MISFOLDED CONFORMATION

Author
item PARAMITHIOTIS, E. - CAPRION PHARMACEUTICALS
item PINARD, M. - CAPRION PHARMACEUTICALS
item LAWTON, T. - IDEXX LABORATORIES
item LABOISSIERE, S. - CAPRION PHARMACEUTICALS
item LEATHERS, S. - IDEXX LABORATORIES
item ZOU, WQ - UNIVERSITY OF TORONTO
item ESTEY, L. - IDEXX LABORATORIES
item LAMONTAGNE, J. - CAPRION PHARMACEUTICALS
item LEHTO, M. - UNIVERSITY OF TORONTO
item KONDEJEWSKI, L. - CAPRION PHARMACEUTICALS
item FRANCOEUR, G. - IDEXX LABORATORIES
item PAPADOPOULOS, M. - CAPRION PHARMACEUTICALS
item HAGHIGHAT, A. - CAPRION PHARMACEUTICALS
item SPATZ, S. - IDEXX LABORATORIES
item HEAD, M. - NATIONAL CREUTZFELDT-JACO
item WILL, R. - NATIONAL CREUTZFELDT-JACO
item IRONSIDE, J. - NATIONAL CREUTZFELDT-JACO
item O'Rourke, Katherine
item TONELLI, Q. - IDEXX LABORATORIES
item LEDEBUR, H. - CAPRION PHARMACEUTICALS
item CHAKRABARTTY, A. - UNIVERSITY OF TORONTO
item CASHMAN, N. - CAPRION PHARMACEUTICALS

Submitted to: Nature Medicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2003
Publication Date: 7/1/2003
Citation: Paramithiotis, E., Pinard, M., Lawton, T., Laboissiere, S., Leathers, S., Zou, W., Estey, L., Lamontagne, J., Lehto, M.T., Kondejewski, L.H., Francoeur, G.P., Papadopoulos, M., Haghighat, A., Spatz, S.J., Head, M., Will, R., Ironside, J., Orourke, K.I., Tonelli, Q., Ledebur, H.C., Chakrabartty, A., Cashman, N.R. 2003. A prion protein epitope selective for the pathologically misfolded conformation. Nature Medicine. 9(7):893-899.

Interpretive Summary: Diagnosis of the transmissible spongiform encephalopathies is based on detection of an abnormal, disease-associated form of a normal protein found in cattle, sheep, and humans. The normal and the abnormal protein share many structural features and most antibodies are unable to distinguish between the forms without extensive treatment of the tissue with enzymes, heat, or acid. The authors describe a method for detecting an area of the protein that changes shape during the shift from the normal to the abnormal form. Using this antibody, they could detect the abnormal form in tissues from mice and sheep without the use of these time-consuming treatment steps. This approach may lead to improved diagnostics and therapeutics for this group of diseases.

Technical Abstract: The transmissible spongiform encephalopathies (prion diseases) are characterized by accumulation of an abnormal isoform of the normal mammalian sialoglycoprotein PrP. The normal and the abnormal isoforms have the same primary structure and conventional antibodies raised to recombinant or synthetic peptides typically fail to distinguish between the forms. The authors describe a technique for identifying epitopes on the surface of the folded protein after conversion to the beta-sheet rich abnormal conformation. An antibody to this epitope could recognize the abnormal isoform in a number of test formats. Conformation-specific antibodies may lead to new diagnostic and therapeutic targets for prion diseases.