Mitchell Center for Alzheimer's Disease and Related Brain Disorders, Department of Neurology, University of Texas Health Science Center, Houston, TX, USA.
Department of Biomedicine, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile.
Mol Psychiatry. 2018 Mar;23(3):777-788. doi: 10.1038/mp.2017.84. Epub 2017 Jun 20.
Transmissible spongiform encephalopathies (TSEs) are fatal neurological disorders caused by prions, which are composed of a misfolded protein (PrP) that self-propagates in the brain of infected individuals by converting the normal prion protein (PrP) into the pathological isoform. Here, we report a novel experimental strategy for preventing prion disease based on producing a self-replicating, but innocuous PrP-like form, termed anti-prion, which can compete with the replication of pathogenic prions. Our results show that a prophylactic inoculation of prion-infected animals with an anti-prion delays the onset of the disease and in some animals completely prevents the development of clinical symptoms and brain damage. The data indicate that a single injection of the anti-prion eliminated ~99% of the infectivity associated to pathogenic prions. Furthermore, this treatment caused significant changes in the profile of regional PrP deposition in the brains of animals that were treated, but still succumbed to the disease. Our findings provide new insights for a mechanistic understanding of prion replication and support the concept that prion replication can be separated from toxicity, providing a novel target for therapeutic intervention.
传染性海绵状脑病（TSEs）是由朊病毒引起的致命神经退行性疾病，朊病毒由错误折叠的蛋白质（PrP）组成，该蛋白质在感染个体的大脑中自我复制，通过将正常朊病毒蛋白（PrP）转化为病理异构体来实现。在这里，我们报告了一种基于产生自我复制但无害的 PrP 样形式（称为抗朊病毒）的新型实验策略，该策略可以与致病性朊病毒的复制竞争。我们的结果表明，用抗朊病毒对感染朊病毒的动物进行预防性接种可延迟疾病的发作，并且在某些动物中完全防止了临床症状和脑损伤的发展。数据表明，单次注射抗朊病毒可消除与致病性朊病毒相关的感染性的约 99％。此外，该治疗方法导致了治疗动物大脑中区域 PrP 沉积模式的显着变化，但仍使动物屈服于疾病。我们的发现为朊病毒复制的机制理解提供了新的见解，并支持这样的概念，即朊病毒复制可以与毒性分离，为治疗干预提供了新的靶标。
