Self- and Cross-Seeding on α-Synuclein Fibril Growth Kinetics and Structure Observed by High-Speed Atomic Force Microscopy
Self- and Cross-Seeding on α-Synuclein Fibril Growth Kinetics and Structure Observed by High-Speed Atomic Force Microscopy
复制标题
通过高速原子力显微镜观察α-突触核蛋白原纤维生长动力学和结构的自播种和交叉播种
DOI：
10.1021/acsnano.0c03074
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发表时间：
2020
期刊：
影响因子：
17.1
通讯作者：
Kenjiro Ono
中科院分区：
文献类型：
--
作者：
Takahiro Watanabe-Nakayama;Maika Nawa;Hiroki Konno;Noriyuki Kodera;Toshio Ando;David B Teplow;Kenjiro Ono
原纤维形成是淀粉样蛋白疾病中的必然过程，其特征在于成核和伸长阶段，导致形成具有交叉β折叠结构的长丝。该过程的动力学以及次级成核的动力学受多种因素控制，包括核（种子）结构、单体构象和生物化学环境。一些纤维状淀粉样蛋白组装体作为朊病毒，从现有朊病毒种子模板的蛋白质单体复制自身。朊病毒株，其特征在于不同的物理化学和病理学特性，也可能形成由于敏感生物体内的模板过程的扰动。了解帕金森病发展和进展过程中发生的扰动的类型和影响是一个需要更多研究的领域。在这里，我们使用高速原子力显微镜来确定α-突触核蛋白原纤维延伸的动力学和结构动力学，所述原纤维延伸由野生型（WT）或突变型α-突触核蛋白与WT或突变型α-突触核蛋白种子的自接种或交叉接种引发。我们发现，交叉播种调制不仅伸长率，但也增长的原纤维的结构。以这种方式产生的一些原纤维具有与其“亲本”种子不同的结构。在其他情况下，根本没有观察到交叉播种。这些发现表明，α-突触核蛋白序列变异体可以通过自身接种或交叉接种产生不同类型的菌株。因此，特定菌株的持久性将取决于原纤维生长的相对速率和由每种菌株形成的原纤维的相对稳定性。
Fibril formation is an obligatory process in amyloid diseases and is characterized by nucleation and elongation phases that result in the formation of long filaments with cross-β sheet structure. The kinetics of this process, as well as that of secondary nucleation, is controlled by a variety of factors, including nucleus (seed) structure, monomer conformation, and biochemical milieu. Some fibrillar amyloid assemblies act as prions, replicating themselves from protein monomers templated by existing prion seeds. Prion strains, which are characterized by distinct physicochemical and pathologic properties, may also form due to perturbation of the templating process within the susceptible organism. Understanding the types and effects of perturbations occurring during the development and progression of Parkinson’s disease is an area requiring more study. Here, we used high-speed atomic force microscopy to determine the kinetics and structural dynamics of α-synuclein fibril elongation initiated by self-seeding or cross-seeding of wild-type (WT) or mutant α-synuclein with WT or mutant α-synuclein seeds. We found that cross-seeding modulated not only elongation rates but also the structures of the growing fibrils. Some fibrils produced in this manner had structures distinct from their “parent” seeds. In other cases, cross-seeding was not observed at all. These findings suggest that α-synuclein sequence variants can produce different types of strains by self- or cross-seeding. Perpetuation of specific strains then would depend on the relative rates of fibril growth and the relative stabilities of the fibrils formed by each strain.