Engineering of dominant-negative mutant of prion protein for therapeutic and diagnostic applications

Completed Research Project

Title / Titel: Engineering of dominant-negative mutant of prion protein for therapeutic and diagnostic applications

Summary / Zusammenfassung: Prion diseases such as Creutzfeldt-Jakob disease (CJD) in human or bovine spongiform encephalopathy (BSE) are fatal neurodegenerative disorders. The presumed causative agent of all prion diseases is an aberrantly folded isoform of the cellular prion protein (PrPC), designated PrPSc, which accumulates in affected brains. To date, there is no available prophylaxis or therapeutic treatment for prion diseases.
Here, I propose to generate a library of PrP mutants, and screen the library for potent dominant-negative mutants by using protein misfolding cyclic amplification (PMCA) assay. Dominant-negative mutants of PrP will be also selected by using prion-infected cells treated with proteasome inhibitors. Therapeutic potential of the most efficient prion-antagonist(s) will be validated by the lentivirus-mediated gene transfer into prion-inoculated wild-type mouse. The selected dominant-negative mutants might also find an application in a highly PrPSc-specific and sensitive detection assay.

Project Leadership and Contacts / Projektleitung und Kontakte

Dr. David Ott (Project Leader)

Funding Source(s) / Unterstützt durch: Forschungskredit der Universität Zürich