Development of a High-Throughput System for Screening of Anti-Prion Molecules

Abstract

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. In order to approach a high-throughput PMCA system, technical aspects in PMCA has been optimized for application of prions from laboratory rodents (i.e., mouse and Syrian hamsters) using a 96-well plate PMCA (96wp-PMCA) platform. Utilizing the 96wp-PMCA technique, a small number of anti-prion and anti-amyloid molecules has been tested against these prion strains using different solvents and at varying concentrations. My results show that regardless of sequence homology, prion strains are differentially responsive to known protein misfolding inhibitors. Continual optimization of PMCA towards a high-throughput system may be used not only for screening therapeutic agents but also for diagnosis

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