NR AOYB
AU Prusiner,S.B.
TI Diagnostics and Therapeutics for Prion Diseases
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Oral sessions OS-01
PT Konferenz-Vortrag
AB Prions cause Creutzfeldt-Jakob disease (CJD) of humans, scrapie of sheep and bovine spongiform encephalopathy (BSE) of cattle. Four new concepts have emerged from studies of prions. First, prions are infectious proteins that are devoid of nucleic acid. Second, prion diseases may be manifest as infectious, genetic and sporadic disorders. Third, prion diseases result from the accumulation of PrPsc, the conformation of which differs substantially from that of its precursor PrPc. Fourth, PrPsc can exist in a variety of different conformations, each of which seems to specify a specific disease phenotype. The conversion of PrPc into PrPsc is not well understood but PrPs with basic residues at 218 or 167 act as dominant negatives that inhibit PrPsc formation. These dominant negative PrPs are likely to act by sequestering an auxiliary molecule involved in prion propagation that has been provisionally designated protein X. Using electron crystallography, constraints on the structure of PrPsc suggest that this isoform may contain a b-helix. There is a great need for sensitive diagnostic procedures as well as effective therapeutics. Extremely sensitive methods for measuring prions should form the basis of antemortem diagnostic tests. Such diagnostic tests would help assure that the human food supply is devoid of prions and identify patients with prion disease before widespread CNS occurs so therapy could be instituted early. Identifying auxiliary molecules such protein X that feature in PrPsc formation may yield new drug targets for development of effective therapeutics that prevent or cure prion diseases.. The most promising lead compound for treating prion disease is the acridine quinacrine with an IC50 of 300nM, which has been improved by creating bis-acridines with IC50 values of ~25nM. Other approaches to therapeutic intervention include a-PrP antibodies, branched polyamines, and compounds mimicking dominant negative PrPs.
AD Stanley B. Prusiner, Institute for Neurodegenerative Diseases, University of California, San Francisco, USA
SP englisch
PO Deutschland