Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India. Electronic address: https://twitter.com/SurabhiMehra5.
Tata Institute of Fundamental Research, Sy. No. 36/P, Gopanpally, Hyderabad 500 046, India.
J Mol Biol. 2022 Oct 15;434(19):167761. doi: 10.1016/j.jmb.2022.167761. Epub 2022 Jul 27.
α-Synuclein (α-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. The mechanism of how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure-function relationship of two polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), based on α-Syn aggregation intermediates. These polymorphs display the structural differences as demonstrated by solid-state NMR and mass spectrometry studies and also possess different cellular activities such as seeding, internalization, and cell-to-cell transfer of aggregates. HMFs, with a compact core structure, exhibit low seeding potency but readily internalize and transfer from one cell to another. The less structured PMFs lack transcellular transfer ability but induce abundant α-Syn pathology and trigger the formation of aggresomes in cells. Overall, the study highlights that the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior.
α-突触核蛋白（α-Syn）在突触核蛋白病中的淀粉样纤维被认为在结构和功能上具有多样性，类似于朊病毒样株。同一前体蛋白的聚集如何导致纤维原纤维多态性的形成机制仍不清楚。在这里，我们基于 α-Syn 聚集中间产物，展示了两种多态物，预成熟纤维（PMFs）和螺旋成熟纤维（HMFs）的结构-功能关系。这些多态物表现出不同的结构差异，如固态 NMR 和质谱研究所示，并且还具有不同的细胞活性，如聚集物的种子、内化和细胞间转移。具有紧凑核心结构的 HMFs 表现出低的种子能力，但容易内化并从一个细胞转移到另一个细胞。结构较少的 PMFs 缺乏细胞间转移能力，但会诱导大量的 α-Syn 病理学，并在细胞中引发聚集物的形成。总的来说，该研究强调了聚集途径中的构象异质性可能导致具有不同朊病毒样行为的纤维原纤维多态物。
