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‐43 CTD ), indicating selective inhibition of α‐Syn aggregation by PRD1.