“Development of High-Throughput System for Screening of Anti-Prion Molecules”

Katherine Do

The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Science

The misfolded prion protein causes and transmits disease in both humans and animals. As other infectious agents, prions display strain variation, which can generate different pathological outcomes in affected individuals. Unfortunately, there are no known therapies for these diseases, which at present are invariably fatal. In this work, the Protein Misfolding Cyclic Amplification technology (PMCA, an in vitro test that replicates minimum quantities of infectious prions) has been modified to screen for small molecules inhibiting prion protein misfolding in a strain-specific manner. Technical aspects in high throughput PMCA (HT-PMCA) has been optimized for application of prions from laboratory rodents (i.e., mouse and hamsters). Utilizing the HT-PMCA technique, a small number of molecules has been tested against these strains using different solvents and at varying concentrations. Our results show that regardless of sequence homology, prion strain are differentially responsive to known protein misfolding inhibitors. Optimization of HT-PMCA may be used not only for screening therapeutic agents but also for diagnosis of large volume of samples.