STRUCTURAL CHARACTERIZATION OF PRION PROTEINS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Prion diseases are unique fatal neurodegenerative diseases caused by novel pathogens termed prions. The only component of prions is an abnormal form of a normal cellular protein termed the prion protein (PrP). The normal form (PrPC) is converted to the pathogenic form (PrPSc) by an as yet unidentified posttranslational process. Mass spectrometry is essential for the detailed analysis of small-scale samples of the prion protein isolated from biological tissues, from recombinant sources and from peptide synthesis. One objective is increase the sensitivity for detection of sub-stoichiometric modifications as it is known that one ID50 of infectivity contains tens of thousands of PrP molecules, not all of which are necessarily pathogenic in their own right. It is also necessary to identify possible accessory molecules that might be present in infectious prions. Comparisons are also required between PrPSc from different prion strains to establish whether strain behavior could arise from covalent differences, e.g. in the N-linked oligosaccharides, which might cause cell specific lectins to target a limited range of cell types, resulting in regional distribution of PrPSc. Results obtained so far suggest that the modification of PrPC involved in the formation of PrPSc is likely conformational rather than chemical.