Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein

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