Kabir M Enamul, Safar Jiri G
Prion. 2014 Jan-Feb;8(1):111-6. doi: 10.4161/pri.27661.
There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and adapt by a prion-like mechanism calls for the reevaluation of therapeutic strategies that target aggregates of misfolded proteins, and argues for new therapeutic approaches that will focus on prior pathogenetic steps.
越来越多的证据表明，包括阿尔茨海默病、帕金森病、额颞叶痴呆和肌萎缩侧索硬化在内的多种人类神经退行性疾病，在大脑中通过朊病毒样的细胞间蛋白质错误折叠诱导而传播。朊病毒可导致人类致命的神经退行性疾病，最常见的是散发性克雅氏病（sCJD）；它们通过将细胞形式的朊病毒蛋白（PrP(C)）转化为错误折叠的致病构象体（PrP(Sc)）来自我复制和传播。人类朊病毒疾病广泛的表型异质性由朊病毒蛋白基因的多态性以及PrP(Sc)的朊病毒株特异性构象决定。值得注意的是，即使不存在信息性核酸，朊病毒在克隆细胞中以及跨越物种屏障时仍可能经历快速适应和进化。在我们对这一过程的研究中，我们分离出了在sCJD中经常共存的不同群体的PrP(Sc)颗粒。人类朊病毒颗粒独立复制，并对初始构象稳定性较低的颗粒进行竞争性选择。暴露于突变底物时，获胜的PrP(Sc)构象体会因稳定性最低而通过对复制率最高的亚群进行自然选择而进一步进化。因此，人类朊病毒的进化和适应是由不同颗粒群体的动态集合实现的，其进化受逐渐不稳定、复制更快的PrP(Sc)构象体的选择支配。这一基本生物学机制可能解释了一些朊病毒在接触靶向PrP(Sc)的化合物后产生的耐药性。由蛋白质错误折叠引起的其他神经退行性疾病的表型异质性是否由错误折叠构象体（毒株）的谱系决定仍有待确定。然而，这些构象体可能通过类似朊病毒的机制进化和适应的前景，要求重新评估针对错误折叠蛋白聚集体的治疗策略，并支持将重点放在先前致病步骤的新治疗方法。
