Pyrimidine RNA Homopolymers Promote Amyloid Formation of a Tau Fragment from the Microtubule-Binding Domain.

Abnormal aggregation of microtubule-associated protein tau into β-sheet-rich fibrils is a hallmark feature of Alzheimer's disease and other tauopathies. The pathogenic P301L mutation within the microtubule-binding domain of tau promotes tau filament formation; however, the molecular mechanisms by which intracellular RNAs regulate this aggregation process remain not fully understood. Here, we investigated the mechanistic effects of RNA homopolymers on the aggregation of a tau fragment peptide (residues 298-317) derived from the microtubule-binding region and its P301L mutant. The results showed that while the wild-type peptide remained resistant to aggregation in the presence of RNA, pyrimidine-rich RNAs (poly(C) and poly(U)) significantly accelerated fibrillation of the P301L mutant. The mutation likely disrupts the local conformational constraints, leading to a more flexible conformation and exposure of hydrophobic residues. This facilitates intermolecular interactions to form β-sheet-rich aggregates after RNA-induced local condensation and alignment of the peptide as a nucleation scaffold for aggregation. In contrast, purine-rich RNAs (poly(A) and poly(G)) had negligible effects on P301L mutant aggregation, suggesting that the specific chemical and conformational properties of RNA, such as base structures, geometrical arrangement, and base stacking, in addition to its polyanionic nature, are critical determinants of its ability to modulate tau peptide amyloid formation. Furthermore, the polycationic molecules spermine and polyarginine effectively delayed or inhibited RNA-induced aggregation, indicating that rationally designed polycations could serve as valuable modulators of RNA-mediated fibrillation within the crucial tau aggregation-prone region.