MRC Laboratory of Molecular Biology, Cambridge, UK.
Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Japan.
FEBS Open Bio. 2021 Apr;11(4):999-1013. doi: 10.1002/2211-5463.13110. Epub 2021 Feb 24.
The propagation of conformational strains by templated seeding is central to the prion concept. Seeded assembly of α-synuclein into filaments is believed to underlie the prion-like spreading of protein inclusions in a number of human neurodegenerative diseases, including Parkinson's disease, dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We previously determined the atomic structures of α-synuclein filaments from the putamen of five individuals with MSA. Here, we used filament preparations from three of these brains for the in vitro seeded assembly of recombinant human α-synuclein. We find that the structures of the seeded assemblies differ from those of the seeds, suggesting that additional, as yet unknown, factors play a role in the propagation of the seeds. Identification of these factors will be essential for understanding the prion-like spreading of α-synuclein proteinopathies.
构象应变的模板引导传播是朊病毒概念的核心。α-突触核蛋白的种子介导组装成纤维被认为是许多人类神经退行性疾病中蛋白质包涵体朊病毒样扩散的基础，包括帕金森病、路易体痴呆（DLB）和多系统萎缩（MSA）。我们之前已经确定了来自五个 MSA 患者壳核的α-突触核蛋白纤维的原子结构。在这里，我们使用这三个大脑的纤维制剂进行重组人α-突触核蛋白的体外种子介导组装。我们发现，种子介导组装的结构与种子的结构不同，这表明其他尚未知的因素在种子的传播中发挥了作用。鉴定这些因素对于理解α-突触核蛋白蛋白病的朊病毒样扩散至关重要。
