The pathological hallmark of synucleinopathies, including Parkinson's disease (PD), is the aggregation of α-synuclein (α-Syn) protein. Even so, tau protein pathology is abundantly found in these diseases. Both α-Syn and tau can exist as polymorphic aggregates, a phenomenon that has been widely studied, mostly in their fibrillar assemblies. We have previously discovered that in addition to α-Syn oligomers, oligomeric tau is also present in the brain tissues of patients with PD and dementia with Lewy bodies (DLB). However, the effect of interaction between polymorphic α-Syn oligomers and tau has not been scrupulously studied. Here, we have explored the structural and functional diversity of distinct α-Syn oligomers, prepared by modifying the protein with dopamine (DA) and docosahexaenoic acid (DHA). The two α-Syn oligomers differed in aggregate size, conformation, sensitivity to proteinase K digestion, tryptic digestion, and toxicity, suggesting them as distinct α-Syn oligomeric strains. We examined their internalization mechanisms in primary neurons and seeding propensity in inducing α-Syn aggregation. Using a combined approach of molecular and cellular techniques, we observed that the tau aggregates cross-seeded with the individual α-Syn oligomeric strains differed in their biochemical and biological properties, suggesting two distinct tau strains. The tau aggregate cross-seeded with the DA-modified α-Syn oligomeric strain possessed a potent intracellular tau seeding propensity. This study provides a comprehensive analysis of unique strain-specific interaction between oligomeric α-Syn and tau. Furthermore, this study allows us to speculate that distinct α-Syn-tau interactions inducing tau aggregation might be an underlying mechanism of neurodegeneration in PD.

中文翻译：

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多巴胺和二十二碳六烯酸修饰的多态性α-突触核蛋白菌株与Tau蛋白差异相互作用。

包括帕金森氏病（PD）在内的突触核蛋白病的病理特征是α-突触核蛋白（α-Syn）蛋白的聚集。即便如此，在这些疾病中仍大量发现tau蛋白病理。α-Syn和tau都可以作为多态聚集体存在，这一现象已被广泛研究，主要存在于它们的纤维状集合体中。我们先前已经发现，除了α-Syn寡聚体外，PD和患有路易体（DLB）的痴呆症患者的脑组织中也存在寡聚tau。然而，尚未仔细研究多态性α-Syn低聚物与tau之间的相互作用的影响。在这里，我们探索了通过用多巴胺（DA）和二十二碳六烯酸（DHA）修饰蛋白质而制备的不同α-Syn低聚物的结构和功能多样性。这两种α-Syn寡聚体在聚集体大小，构象，对蛋白酶K消化的敏感性，胰蛋白酶消化和毒性方面有所不同，表明它们是不同的α-Syn寡聚菌株。我们检查了它们在初级神经元中的内在化机制和诱导α-Syn聚集的播种倾向。使用分子和细胞技术的组合方法，我们观察到与单个α-Syn低聚物菌株交叉播种的tau聚集体的生化和生物学特性不同，表明存在两种截然不同的tau菌株。与DA修饰的α-Syn寡聚菌株交叉播种的tau聚集体具有有效的胞内tau播种倾向。这项研究提供了寡聚α-Syn和tau之间独特的菌株特异性相互作用的全面分析。此外，