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

## TL;DR

This paper reviews how TDP-43 undergoes phase separation and its role in forming cellular structures and disease-related inclusions.

## Contribution

The paper provides a comprehensive review of TDP-43's phase separation mechanisms and its connection to solid inclusion formation in disease.

## Key findings

- Full-length TDP-43 needs RNA or chaperones to form stable liquid droplets in vitro.
- TDP-43 is a key component of membraneless organelles and may contribute to pathological solid inclusions.
- There is ongoing debate about whether TDP-43 assemblies act as reservoirs for disease-related inclusions.

## 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.