Departamento de Química Orgánica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (UBA), CIHIDECAR CONICET, Buenos Aires, Argentina.
Biophys J. 2012 Mar 7;102(5):1127-36. doi: 10.1016/j.bpj.2012.01.051. Epub 2012 Mar 6.
The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ~0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.
α-突触核蛋白的聚集与帕金森病的进展有关。我们已经确定了介导整体机制早期阶段的亚微米超分子结构。通过原子力显微镜（AFM）引导的荧光探针，捕获并表征了亚稳定中间态之间结构转化的顺序，该探针对前淀粉样物种敏感。一种新的~0.3-0.6μm 分子组装体，称为 acuna，具有独特的分段和丝状毛茸茸边缘的纤维进行成核、扩展和释放。这些毛茸茸的纤维作为成熟淀粉样原纤维的前体。冷冻电子断层扫描解析了 acuna 的内部结构，作为高度凝聚胶体物质的支架，由薄珠串互联，原子力显微镜认为这是绒毛状的。基于综合数据，我们提出了一个连续的机制，包括分子、胶体和纤维阶段，通过与不同温度依赖性和不同超分子形式的反应连接。我们期望基于这些对 α-突触核蛋白和中间产物聚集机制的新见解，为帕金森病和相关神经退行性疾病开发新的诊断和治疗方法，其中一些可能会导致和/或增强神经毒性。
