Tau Interacts with the C-Terminal Region of α-Synuclein, Promoting Formation of Toxic Aggregates with Distinct Molecular Conformations

An increasing body of evidence suggests that aggregation -prone proteins associated with various neurodegenerative diseases synergistically promote their mutual aggregation, leading to the co-occurrence of multiple neurodegenerative diseases in the same patient. Here we investigated teh molecular basis of synergistic interactions between the two pathological proteins, tau and alpha-synuclein, using various biophysical techniques including transmission electron microscopy (TEM), circular dichroism (CD), and solution and solid-state NMR. Our biophysical analyses of alpha-synuclein aggregation in the absence and presence of tau reveal that tau monomers promote the formation of alpha-synuclein oligomers and subsequently fibril formation. Solution NMR results also indicate that monomeric forms of tau selectively interact with the C-terminal region of the alpha-synuclein monomer, accelerating alpha-synuclein aggregation. In addition, a combined use of TEM and solid-state NMR spectroscopy reveals that the synergistic interactions lead to the formation of toxic alpha-synuclein aggregates with a distinct morphology and molecular conformation. The filamentous alpha-synuclein aggregates as well as alpha-synuclein monomers were also able to induce tau aggregation.