Genesis of Mammalian Prions: From Non-infectious Amyloid Fibrils to a Transmissible Prion Disease

The transmissible agent of prion disease consists of a prion protein in its abnormal, β-sheet rich state (PrPSc), which is capable of replicating itself according to the template-assisted mechanism. This mechanism postulates that the folding pattern of a newly recruited polypeptide chain accurately reproduces that of a PrPSc template. Here we report that authentic PrPSc and transmissible prion disease can be generated de novo in wild type animals by recombinant PrP (rPrP) amyloid fibrils, which are structurally different from PrPSc and lack any detectable PrPSc particles. When induced by rPrP fibrils, a long silent stage that involved two serial passages preceded development of the clinical disease. Once emerged, the prion disease was characterized by unique clinical, neuropathological, and biochemical features. The long silent stage to the disease was accompanied by significant transformation in neuropathological properties and biochemical features of the proteinase K-resistant PrP material (PrPres) before authentic PrPSc evolved. The current work illustrates that transmissible prion diseases can be induced by PrP structures different from that of authentic PrPSc and suggests that a new mechanism different from the classical templating exists. This new mechanism designated as “deformed templating” postulates that a change in the PrP folding pattern from the one present in rPrP fibrils to an alternative specific for PrPSc can occur. The current work provides important new insight into the mechanisms underlying genesis of the transmissible protein states and has numerous implications for understanding the etiology of neurodegenerative diseases.

朊病毒病的传染性病原体由处于异常、富含β折叠构象的朊蛋白（PrPSc）组成，该蛋白可通过模板辅助机制完成自我复制。该机制假定，新募集的多肽链的折叠模式可精准复刻PrPSc模板的折叠模式。本研究报道，重组朊蛋白（rPrP）淀粉样纤维可在野生型动物体内从头生成具有传染性的PrPSc与可传播性朊病毒病——这类淀粉样纤维的结构与PrPSc存在显著差异，且未携带任何可检测到的PrPSc颗粒。当由rPrP纤维诱导发病时，临床症状出现前存在一段漫长的静默期，该阶段需经历两次连续传代。一旦疾病发作，其临床、神经病理及生化特征均具有独特性。在天然PrPSc演化形成前，疾病的漫长静默期伴随抗蛋白酶K的朊蛋白（PrPres）的神经病理特性与生化特征发生显著改变。本研究表明，可传播性朊病毒病可由与天然PrPSc结构不同的朊蛋白结构诱导产生，并提示存在一种不同于经典模板机制的新机制。这一新机制被命名为“变形模板机制”，其核心假定为：PrP的折叠模式可从rPrP纤维的构象转变为PrPSc特有的替代构象。本研究为可传播性蛋白状态的形成机制提供了重要新见解，并对理解神经退行性疾病的病因学具有多重重要启示。