Translational regulation in the brain by TDP-43 phase separation

Ju Gao, Luwen Wang, Xiaojia Ren, Justin R. Dunn, Ariele Peters, Masaru Miyagi, Hisashi Fujioka, Fangli Zhao, Candice Askwith, Jingjing Liang, Xinglong Wang

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The in vivo physiological function of liquid–liquid phase separation (LLPS) that governs non–membrane-bound structures remains elusive. Among LLPS-prone proteins, TAR DNA-binding protein of 43 kD (TDP-43) is under intense investigation because of its close association with neurological disorders. Here, we generated mice expressing endogenous LLPS-deficient murine TDP-43. LLPS-deficient TDP-43 mice demonstrate impaired neuronal function and behavioral abnormalities specifically related to brain function. Brain neurons of these mice, however, did not show TDP-43 proteinopathy or neurodegeneration. Instead, the global rate of protein synthesis was found to be greatly enhanced by TDP-43 LLPS loss. Mechanistically, TDP-43 LLPS ablation increased its association with PABPC4, RPS6, RPL7, and other translational factors. The physical interactions between TDP-43 and translational factors relies on a motif, the deletion of which abolished the impact of LLPS-deficient TDP-43 on translation. Our findings show a specific physiological role for TDP-43 LLPS in the regulation of brain function and uncover an intriguing novel molecular mechanism of translational control by LLPS.

Original languageEnglish (US)
Article numbere202101019
JournalJournal of Cell Biology
Volume220
Issue number10
DOIs
StatePublished - Oct 4 2021

Keywords

  • Neuroscience
  • Protein homeostasis

ASJC Scopus subject areas

  • Cell Biology

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