NR AXKI
AU Caughey,B.
TI Prion Protein Aggregation, Amplification and Inhibition
QU International Conference - Prion 2007 (26.-28.9.2007) Edinburgh International Conference Centre, Edinburgh, Scotland, UK - Book of Abstracts: Invited Speakers S1.1
IA http://www.prion2007.com/pdf/Prion Book of Abstracts.pdf
PT Konferenz-Vortrag
AB In TSE/prion diseases, normal prion protein (PrPc) undergoes a conformational conversion into oligomeric forms that are associated with infectivity (e.g., PrPsc). Comparisons of a range of PrPsc-containing particles revealed that the most infectious particles per unit protein are non-fibrillar oligomers of ~600 kDa rather than larger amyloid fibrils. Attempts to detect PrPsc with ultrasensitive PMCA-like amplification reactions using recombinant E. coli-expressed PrPc as a substrate will be presented. Recent progress in our attempts to reduce the risks posed by TSE diseases will also be discussed. The apparent infectivity of contaminated samples can be decreased by orders of magnitude by mixing with cyclic tetrapyrroles or non-CpG phosphorothioate oligonucleotides. Prophylactic treatments of rodents with these compounds quadrupled their survival times after high-dose intraperitoneal inoculations with scrapie. Direct intracerebral treatments with a mixture of a porphyrin and pentosan polysulfate beginning weeks after high-dose intracerebral inoculations of scrapie substantially increased survival times over treatments with either compound alone. Thus, such treatments show efficacy against established brain infections. Mechanistic studies suggest a common mechanism of action for several of the most effective classes of anti-TSE compounds. This mechanism involves inhibition of conversion by binding to PrPc, causing it to cluster and be internalized from the cell surface. Potential physiological roles of PrPc binding to natural homologs of prophylactic conversion inhibitors such as porphyrins (e.g. hemin), oligonucleotides, and sulfated glycosaminoglycans will be considered.
AD Byron Caughey, Rocky Mountain Labs, NIAID, NIH, LPVD, USA
SP englisch
PO Schottland