Mechanistic description
Synthetic RNA aptamers designed to competitively bind TDP-43’s RNA recognition motifs could prevent its interaction with tau and α-synuclein mRNAs, thereby blocking the RNA-mediated cross-seeding mechanism. This approach targets the unique ability of TDP-43 to recruit other proteins through RNA scaffolding.
Evidence for (3)
TDP-43 binds tau mRNA and regulates its translation
RNA molecules can template protein aggregation and cross-seeding
Synthetic aptamers successfully modulate TDP-43 RNA interactions
Evidence against (3)
TDP-43 RNA binding is essential for normal cellular function, making competitive inhibition potentially toxic
RNA aptamers show poor CNS penetration and rapid degradation
TDP-43 pathology often involves loss rather than gain of RNA binding function