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

• Published in: Molecular neurobiology 2020-06, Vol.57 (6), p.2741-2765
• Main Authors: Sengupta, Urmi, Puangmalai, Nicha, Bhatt, Nemil, Garcia, Stephanie, Zhao, Yingxin, Kayed, Rakez
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Biomedical and Life Sciences; Biomedicine; Cell Biology; Cell Line, Tumor; Cell Survival - drug effects; Dementia disorders; Docosahexaenoic acid; Docosahexaenoic Acids - pharmacology; Dopamine; Dopamine - pharmacology; Endopeptidase K; Humans; Internalization; Lewy bodies; Movement disorders; Neurobiology; Neurodegeneration; Neurodegenerative diseases; Neurology; Neurons - drug effects; Neurons - metabolism; Neurosciences; Neurotoxicity; Parkinson Disease - metabolism; Parkinson's disease; Protein Aggregates - drug effects; Protein Aggregation, Pathological - metabolism; Proteinase; Proteins; Structure-function relationships; Synuclein; Tau protein; tau Proteins - metabolism
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-020-01913-6

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.