RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo

Natalie Scherer, Cindy Maurel, Matthew Graus, Luke McAlary, Grant Richter, Rowan Radford, Alison Hogan, Emily Don, Albert Lee, Justin Yerbury, Mathias Francois, Roger Chung, Marco Morsch

Research output: Contribution to journalArticlepeer-review

Abstract

Insoluble cytoplasmic aggregate formation of the RNA-binding protein TDP-43 is a major hallmark of neurodegenerative diseases including Amyotrophic Lateral Sclerosis. TDP-43 localizes predominantly in the nucleus, arranging itself into dynamic condensates through liquid-liquid phase separation (LLPS). Mutations and post-translational modifications can alter the condensation properties of TDP-43, contributing to the transition of liquid-like biomolecular condensates into solid-like aggregates. However, to date it has been a challenge to study the dynamics of this process in vivo. We demonstrate through live imaging that human TDP-43 undergoes nuclear condensation in spinal motor neurons in a living animal. RNA-binding deficiencies as well as post-translational modifications can lead to aberrant condensation and altered TDP-43 compartmentalization. Single-molecule tracking revealed an altered mobility profile for RNA-binding deficient TDP-43. Overall, these results provide a critically needed in vivo characterization of TDP-43 condensation, demonstrate phase separation as an important regulatory mechanism of TDP-43 accessibility, and identify a molecular mechanism of how functional TDP-43 can be regulated.

Original languageEnglish
JournalNucleic Acids Research
Early online date21 Feb 2024
DOIs
Publication statusE-pub ahead of print - 21 Feb 2024

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