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)

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Abstract

In >95% of cases 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.This article has an associated First Person interview with the first author of the paper.

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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