G-quadruplex sequence dictates tau oligomerization and fibril morphology

Abstract

Previous studies have identified that non-canonical nucleic acid structures known as G-quadruplexes (G4s) modulate protein aggregation and could play major roles in neurodegenerative diseases. Here we examine the presence and protein oligomerization activity of G4s that are enriched in human hippocampal aggregates. We found these G4s to be powerful, sequence-specific modulators of aggregation. Different G4s facilitated aggregate propagation in cells, caused tau to form distinct protein oligomer populations, and seeded tau fibrils with different fibril structure and length. This study highlights the importance of nucleic acid composition within aggregates, where small changes in nucleotide sequence and topology can vastly alter protein interactions, oligomerization, and fibrillization.