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

Area of Science:

• Neuroscience
• Biochemistry
• Molecular Biology

Background:

• Misfolded protein aggregation, including alpha-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43), is central to neurodegenerative diseases like Parkinson's and frontotemporal dementia.
• Heterotypic protein aggregates are recognized for their high cytotoxicity.
• Co-occurrence of α-Syn, TDP-43, and tau pathologies is frequent in neurodegenerative conditions.

Purpose of the Study:

• To investigate whether the first prion-like domain (PRD1) of CPEB3 modulates the aggregation of α-Syn and TDP-43.
• To determine the specific interactions of PRD1 with α-Syn and TDP-43 aggregates.

Main Methods:

• Nuclear magnetic resonance (NMR) relaxation experiments to probe direct interactions.
• Phase separation assays to evaluate liquid-liquid phase separation (LLPS)-mediated aggregation.
• Analysis of interactions with the amyloid core of α-Syn and the C-terminal domain of TDP-43 (TDP-43_CTD).

Main Results:

• PRD1 directly interacts with the amyloid core of α-Syn, leading to suppressed aggregation.
• Phase separation assays demonstrated that PRD1 delays α-Syn aggregation mediated by LLPS.
• No direct interaction was observed between PRD1 and TDP-43_CTD.

Conclusions:

• CPEB3 PRD1 selectively inhibits α-Syn aggregation.
• PRD1's interaction with α-Syn amyloid core and its effect on LLPS suggest a specific mechanism for neuroprotection.
• These findings highlight PRD1 as a potential therapeutic target for α-Syn-related neurodegenerative diseases.