Investigating the Potential Role of α-Synuclein in Tau Aggregation and Toxicity

A group of neurodegenerative diseases that are pathologically characterized by the presence of intracellular abnormal aggregation of α-Synuclein (α-Syn) in Lewy bodies (LBs) and Lewy neurites (LNs), are collectively known as synucleinopathies. Even so, tau protein pathology is abundantly found in these diseases. Apart from Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), LBs and LNs have been reported in Alzheimer’s disease (AD) patients as well. Both α-Syn and tau can exist as polymorphic aggregates, and this phenomenon has been widely studied, mostly in their fibrillar assemblies. Growing evidence suggests that intermediate metastable oligomeric assemblies of several amyloidogenic proteins, including α-Syn and tau are actual neurotoxic species. However, little is known about the structural and functional heterogeneity among α-Syn oligomers occurring in different diseases. Moreover, the functional crosstalk between these toxic oligomers has not been scrupulously studied. Here, by using biochemical, biophysical and cell-based techniques, I have studied the structural and functional diversity of distinct recombinant α-Syn oligomers, prepared by modifying the protein with two physiological inducers, dopamine (DA) and docosahexaenoic acid (DHA). The two recombinant 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. I have also analyzed brain-derived α-Syn oligomers (BDSOs) from AD, DLB and PD brain tissues. I observed that disease associated BDSOs were diverse in their functional properties. Notably, they can be uptaken via gap junction protein Cx50 in the primary neurons, thus suggesting a unique mechanism that might be involved in the oligomers mediated toxicity. Additionally, both recombinant and brain-derived α-Syn oligomeric strains effectively cross-seeded tau aggregates with diverse biochemical, biophysical and biological properties. Interestingly, BDSOs cross-seeded tau aggregates were more potent seeds causing cellular tau aggregation than the ones cross-seeded with recombinant α-Syn oligomeric strains. The findings here represent a significant step to elucidate the toxic interplay between α-Syn oligomeric strains and tau, altering the aggregation profiles and nature of the amyloid deposits. This will lay the groundwork for more successful therapeutic interventions by targeting multiple candidate molecules, such as α-Syn and tau in diseases.