TDP-43 stabilizes G3BP1 mRNA: Relevance to amyotrophic lateral sclerosis/frontotemporal dementia

Hadjara Sidibé, Yousra Khalfallah, Shangxi Xiao, Nicolás B. Gómez, Hana Fakim, Elizabeth M.H. Tank, Geneviève Di Tomasso, Eric Bareke, Anaïs Aulas, Paul M. McKeever, Ze'ev Melamed, Laurie Destroimaisons, Jade Emmanuelle Deshaies, Lorne Zinman, J. Alex Parker, Pascale Legault, Martine Tétreault, Sami J. Barmada, Janice Robertson, Christine Vande Velde*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

TDP-43 nuclear depletion and concurrent cytoplasmic accumulation in vulnerable neurons is a hallmark feature of progressive neurodegenerative proteinopathies such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cellular stress signalling and stress granule dynamics are now recognized to play a role in ALS/FTD pathogenesis. Defective stress granule assembly is associated with increased cellular vulnerability and death. Ras-GAP SH3-domain-binding protein 1 (G3BP1) is a critical stress granule assembly factor. Here, we define that TDP-43 stabilizes G3BP1 transcripts via direct binding of a highly conserved cis regulatory element within the 3ʹ untranslated region. Moreover, we show in vitro and in vivo that nuclear TDP-43 depletion is sufficient to reduce G3BP1 protein levels. Finally, we establish that G3BP1 transcripts are reduced in ALS/FTD patient neurons bearing TDP-43 cytoplasmic inclusions/nuclear depletion. Thus, our data indicate that, in ALS/FTD, there is a compromised stress granule response in disease-affected neurons due to impaired G3BP1 mRNA stability caused by TDP-43 nuclear depletion. These data implicate TDP-43 and G3BP1 loss of function as contributors to disease.

Original languageAmerican English
Pages (from-to)3461-3476
Number of pages16
JournalBrain
Volume144
Issue number11
DOIs
StatePublished - 1 Nov 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Keywords

  • G3BP1
  • TDP-43
  • amyotrophic lateral sclerosis
  • frontotemporal dementia
  • stress granules

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