NR AWGB
AU Griffin,J.K.; Lehto,M.T.; Terry,L.A.; Jackman,R.; Li,L.; Yousefil,M.; Cashman,N.R.
TI PrPsc exposure of tyr-tyr-arg: marker, probe and treatment target
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Oral sessions ORAL-48
PT Konferenz-Vortrag
AB The prion diseases are characterized by the template-directed conversion of normal cellular prion protein (PrPc) into an abnormal, protease-resistant isoform (PrPsc). Conversion of prion protein in disease is associated with the loss of certain molecular surface epitopes, and the acquisition of others, including the tripeptide motif Tyr-Tyr-Arg. Dendritic cells from scrapie-infected sheep display cell surface immunoreactivity for Tyr-Tyr-Arg, consistent with the key role of these peripheral immunocytes in prion neuroinvasion. Exposure of the Tyr-Tyr-Arg epitope in PrP misfolding puts constraints on mechanisms of PrP disease conversion, and suggests that the short beta sheet of PrPc must dissociate as an intermediate to PrPsc conversion. Misfolding-associated exposure of TyrTyr-Arg provides a unique immunotherapy target. We have demonstrated that: 1) monoclonal antibodies directed against the Tyr-Tyr-Arg epitope deplete scrapie-infected ScN2a cells of PrPres, the protease-resistant core of PrPsc; 2) the infectious titre of 301V prion inocula treated ex vivo with Tyr-Tyr-Arg mAbs is reduced by 5-10 fold in subsequent mouse bioassay; and 3) CD1 wild-type mice immunized with Tyr-Tyr-Arg peptides are partially protected against experimental transmission of RML scrapie by intracranial inoculation. The Tyr-Tyr-Arg research program provides a prototype for neo-epitopes exposed during protein misfolding, which may have applications for other posttranslational disorders of the proteome.
AD J.K. Griffin, L. Li: Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada; M.T. Lehto: Centre for Research in Neurodegenerative Diseases, University of Toronto, and Amorfix Life Sciences Ltd., Toronto, Ontario, Canada; L.A. Terry, R. Jackman: Veterinary Laboratories Agency, DEFRA, New Haw, Surrey, UK; M. Yousefi: Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, Canada, and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada; N.R. Cashman: Centre for Research in Neurodegenerative Diseases, University of Toronto, Amorfix Life Sciences Ltd., Toronto, Ontario, Canada and Brain Research Centre, University of British Columbia, Vancouver, BC, Canada
SP englisch
PO Italien