On scrapie interference and artificial prions

The mechanisms responsible for neuronal death in transmissible spongiform encephalopathies (TSEs) are still not completely understood, and at least two major hypotheses have been formulated, based on the peculiar aspects of prion protein biology. In fact, the neuronal spreading of the prion conformational change may lead either to gain toxic properties, or to loose the normal function of this protein. In order to investigate the relative contribution of these two opposite mechanisms, two theoretical approaches may be proposed: RNA interference (RNAi) and artificial prion engineering. In fact, RNAi techniques offer now an extremely exciting new toot for investigating the effects of gene silencing both in prion, and other neurological disorders. On the other hand, the gain-of-toxic-function hypothesis might be definitely evaluated by creating an artificial prion choosing a protein target whose loss of function could be bypassed in the experimental set. In this paper the two aforementioned strategies are outlined, briefly discussing the consequent implications for TSE therapy. (C) 2004 Elsevier Ltd. All rights reserved.