Polymorphic α-Synuclein Strains Modified by Dopamine and Docosahexaenoic Acid Interact Differentially with Tau Protein
Urmi Sengupta, Nicha Puangmalai, Nemil Bhatt, Stephanie García, Yingxin Zhao, Rakez Kayed
Abstract
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.