BACKGROUND: The coexistence of α-synuclein and tau aggregates in several neurodegenerative disorders, including Parkinson’s disease and Alzheimer’s disease, raises the possibility that a seeding mechanism is involved in disease progression. METHODS: To further investigate the role of α-synuclein in the tau aggregation pathway, we performed a set of experiments using both recombinant and brain-derived tau and α-synuclein oligomers to seed monomeric tau aggregation in vitro and in vivo. Brain-derived tau oligomers were isolated from well-characterized cases of progressive supranuclear palsy (n = 4) and complexes of brain-derived α-synuclein/tau oligomers isolated from patients with Parkinson’s disease (n = 4). The isolated structures were purified and characterized by standard biochemical methods, then injected into Htau mice (n = 24) to assess their toxicity and role in tau aggregation. RESULTS: We found that α-synuclein induced a distinct toxic tau oligomeric strain that avoids fibril formation. In vivo, Parkinson’s disease brain-derived α-synuclein/tau oligomers administered into Htau mouse brains accelerated endogenous tau oligomer formation concurrent with increasing cell loss. CONCLUSIONS: Our findings provide evidence, for the first time, that α-synuclein enhances the harmful effects of tau, thus contributing to disease progression.

中文翻译：

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α-突触核蛋白寡聚体诱导独特的有毒 tau 菌株

背景：α-突触核蛋白和 tau 聚集体在几种神经退行性疾病（包括帕金森病和阿尔茨海默病）中的共存增加了一种可能，即播种机制参与了疾病进展。方法：为了进一步研究 α-突触核蛋白在 tau 聚集途径中的作用，我们使用重组和脑源性 tau 和 α-突触核蛋白寡聚体进行了一系列实验，以在体外和体内产生单体 tau 聚集。脑源性 tau 寡聚体是从进行性核上性麻痹（n = 4）和脑源性 α-突触核蛋白/tau 寡聚体复合物的充分表征病例中分离出来的，这些复合物从帕金森病患者（n = 4）中分离出来。通过标准生化方法对分离的结构进行纯化和表征，然后注射到 Htau 小鼠 (n = 24) 中以评估它们在 tau 聚集中的毒性和作用。结果：我们发现 α-突触核蛋白诱导了一种独特的有毒 tau 寡聚菌株，可避免原纤维形成。在体内，帕金森氏病脑源性 α-突触核蛋白/tau 寡聚体给药到 Htau 小鼠大脑中，加速了内源性 tau 寡聚体的形成，同时增加了细胞损失。结论：我们的研究结果首次提供了证据，即 α-突触核蛋白增强了 tau 的有害影响，从而促进了疾病进展。帕金森氏病脑源性 α-突触核蛋白/tau 寡聚体施用到 Htau 小鼠大脑中，加速了内源性 tau 寡聚体的形成，同时增加了细胞损失。结论：我们的研究结果首次提供了证据，即 α-突触核蛋白增强了 tau 的有害影响，从而促进了疾病进展。帕金森氏病脑源性 α-突触核蛋白/tau 寡聚体施用到 Htau 小鼠大脑中，加速了内源性 tau 寡聚体的形成，同时增加了细胞损失。结论：我们的研究结果首次提供了证据，即 α-突触核蛋白增强了 tau 的有害影响，从而促进了疾病进展。