What question did this study set out to answer?

This review aims to clarify how TDP-43 undergoes liquid–liquid phase separation and contributes to the formation of solid inclusions associated with neurodegenerative diseases.

February 2, 2026Open Access

Understanding liquid–liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation

Key Points

This review aims to clarify how TDP-43 undergoes liquid–liquid phase separation and contributes to the formation of solid inclusions associated with neurodegenerative diseases.
Reviewed physicochemical fundamentals of TDP-43 phase separation in vitro.
Analyzed the need for RNA and chaperones for stable droplet formation.
Discussed TDP-43-containing membraneless organelles and their implications.
Full-length TDP-43 requires RNA or chaperones to form stable liquid droplets.
TDP-43 forms neuronal cytoplasmic inclusions linked to neurodegenerative diseases.
Debate exists on whether membraneless organelles act as reserves for pathogenic solid inclusion formation.

Abstract

Abstract Phase separation is an important process in biology associated with formation of membraneless organelles but possibly related to the emergence of solid inclusions. TDP-43 is a largely studied paradigmatic case, as it forms neuronal cytoplasmic inclusions in neurodegenerative diseases and is an essential component of many membraneless organelles. Here, we review the physicochemical fundamentals of liquid–liquid phase separation (LLPS) of TDP-43 and its fragments in vitro, showing that full-length TDP-43 requires RNA or chaperones to form stable liquid droplets. We describe TDP-43-containing membraneless organelles and the debate on whether these assemblies represent reservoirs for pathological solid inclusion formation.

Understanding liquid–liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation

Key Points

Abstract

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