TDP-43, a protein central to amyotrophic lateral sclerosis, is destabilized by tankyrase-1 and -2

Leeanne McGurk (Lead / Corresponding author), Olivia Rifai, Nancy M. Bonini (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
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Abstract

In >95% of amyotrophic lateral sclerosis (ALS) and ~45% of frontotemporal degeneration (FTD), the RNA/DNA-binding protein TDP-43 is cleared from the nucleus and abnormally accumulates in the cytoplasm of affected brain cells. Although the cellular triggers of disease pathology remain enigmatic, mounting evidence implicates the poly(ADP-ribose) polymerases (PARPs) in TDP-43 neurotoxicity. Here we show that inhibition of the PARP enzymes Tankyrase 1 and Tankyrase 2 (referred to as Tnks-1/2) protect primary rodent neurons from TDP-43-associated neurotoxicity. We demonstrate that Tnks-1/2 interacts with TDP-43 via a newly defined Tankyrase-binding domain. Upon investigating the functional effect, we find that interaction with Tnks-1/2 inhibits the ubiquitination and proteasomal turnover of TDP-43, leading to its stabilization. We further show that proteasomal turnover of TDP-43 occurs preferentially in the nucleus; our data indicate that Tnks-1/2 stabilizes TDP-43 by promoting cytoplasmic accumulation, which sequesters the protein from nuclear proteasome degradation. Thus, Tnks-1/2 activity modulates TDP-43 and is a potential therapeutic target in diseases associated with TDP-43, such as ALS and FTD.

Original languageEnglish
JournalJournal of Cell Science
Volume133
Issue number12
Early online date14 May 2020
DOIs
Publication statusPublished - 23 Jun 2020

Keywords

  • ALS
  • FTD
  • PARP
  • Poly(ADP-ribose)
  • Proteasome
  • Ubiquitin

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