Exploring the Potential Interaction between the Functional Prion Protein CPEB3 and the Amyloidogenic Pathogenic Protein Tau.

Abstract

Abnormal aggregation of tau protein is pathologically linked to Alzheimer's disease, while the aggregation of the prion-like RNA-binding protein (RBP) CPEB3 is functional and is associated with long-term memory. However, the interaction between these two memory-related proteins has not yet been explored. Our residue-specific NMR relaxation study revealed that the first prion domain of CPEB3 (PRD1) interacts with the ³⁰⁶VQIVYKPVDLSKV³¹⁸ segment of tau and prevents the aggregation of tau-K18. Notably, this interaction is synergistic as it not only inhibits tau-K18 aggregation but also enhances PRD1 fibril formation. We also studied the interaction of different PRD1 subdomains with tau-K18 to elucidate the precise region of PRD1 that inhibits tau-K18 aggregation. This revealed that the PRD1-Q region is responsible for preventing tau-K18 aggregation. Inspired by this, we synthesized a 15 amino acid Poly-Q peptide that inhibits tau-K18 aggregation, suggesting its potential as a small drug-like molecule for Alzheimer's disease therapeutics.