TDP-43 Aggregation: The Healthy-Toxic Balance of the Prion-Like Domain

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• TAR DNA-binding protein 43 (TDP-43) is an RNA-binding protein vital for RNA metabolism.
• Pathological TDP-43 aggregates characterize neurodegenerative diseases like ALS and FTLD.
• TDP-43 undergoes physiological liquid-liquid phase separation (LLPS) for normal function.

Purpose of the Study:

• To review the structural basis of TDP-43's dual polymerization behavior.
• To explore the role of the prion-like domain in TDP-43 aggregation.
• To connect physiological and pathological TDP-43 polymerization in proteinopathies.

Main Methods:

• Literature review of structural and functional studies on TDP-43.
• Analysis of factors influencing TDP-43 liquid-liquid phase separation (LLPS).
• Comparison of TDP-43 with prion proteins.

Main Results:

• TDP-43 polymerization is regulated by its prion-like domain, similar to prion proteins.
• Physiological TDP-43 assemblies are essential for RNA processing.
• Dysregulated LLPS, due to mutations or modifications, drives pathogenic aggregation.

Conclusions:

• TDP-43 polymerization has both physiological and pathological roles.
• The prion-like domain is central to TDP-43's aggregation propensity.
• Modulating TDP-43 LLPS offers therapeutic strategies for TDP-43 proteinopathies.