CPEB3 selectively inhibits α-synuclein aggregation without modulating TDP-43 pathology.

Abnormal accumulation of misfolded proteins is a hallmark of neurodegenerative diseases. Amyloid aggregation of α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) contributes to Parkinson's disease and frontotemporal dementia, respectively. The heterotypic aggregates are increasingly recognized as highly cytotoxic. Given the frequent co-occurrence of α-Syn, TDP-43, and tau pathologies, we examined whether the first prion-like domain (PRD1) of CPEB3 modulates α-Syn and TDP-43 aggregation. Nuclear magnetic resonance (NMR) relaxation experiments revealed a direct interaction between PRD1 and the amyloid core of α-Syn, suppressing its aggregation, while phase separation assays showed delayed liquid-liquid phase separation (LLPS) -mediated α-Syn aggregation. In contrast, no interaction was detected with the C-terminal domain of TDP-43 (TDP-43CTD), indicating selective inhibition of α-Syn aggregation by PRD1.