Tremolizzo Lucio, Rodriguez-Menendez Virginia, Ferrarese Carlo
Laboratory of Neurobiology, D.N.T.B., University of Milano-Bicocca, S.Gerardo Hospital, Villa Serena 4 p. Sud, via Donizetti 106, 20052 Monza (MI), Italy.
Med Hypotheses. 2004;63(5):838-40. doi: 10.1016/j.mehy.2004.02.054.
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 tool 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.
可传播性海绵状脑病（TSEs）中神经元死亡的机制仍未完全明确，基于朊病毒蛋白生物学的独特方面，至少已形成了两种主要假说。事实上，朊病毒构象变化的神经元传播可能导致获得毒性特性，或丧失该蛋白的正常功能。为了研究这两种相反机制的相对作用，可以提出两种理论方法：RNA干扰（RNAi）和人工朊病毒工程。实际上，RNAi技术现在为研究朊病毒及其他神经疾病中的基因沉默效应提供了一个极其令人兴奋的新工具。另一方面，通过创建一种人工朊病毒，选择一个在实验设置中其功能丧失可被绕过的蛋白质靶点，可能会明确评估毒性功能获得假说。本文概述了上述两种策略，并简要讨论了其对TSE治疗的后续影响。
