Overexpression of TDP-43 causes partially p53-dependent G2/M arrest and p53-independent cell death in HeLa cells

Kikyo Lee, Hiroaki Suzuki, Sadakazu Aiso, Masaaki Matsuoka

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

It has been hypothesized that the dysregulation of transactive response DNA-binding protein-43 (TDP-43) in neurons is closely linked to the pathogenesis of amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitinated inclusions. However, it remains undefined whether the dysregulation of TDP-43 in non-neuronal cells, such as glial cells, contributes to the pathogenesis of these neurodegenerative diseases. Primarily using HeLa cells, we show that a low-grade overexpression of TDP-43, 2- to 5-fold greater than endogenous expression, which is thought to mimic the gain of function of TDP-43, induced cell cycle arrest at the G2/M phase and cell death in cultured non-neuronal cells. Since the activation of p53 may induce G2/M arrest and/or cell death in many abnormal situations, we examined the mechanism underlying G2/M arrest from the standpoint of p53 regulation. It was determined that the TDP-43-induced G2/M arrest was attenuated, while TDP-43-induced death was not attenuated, in cells in which the p53 function was compromised. These data collectively indicate that TDP-43 causes G2/M arrest in a partially p53-dependent manner and it causes cell death in a p53-independent manner in cycling cells. Because it is likely that the impaired proliferation in glial cells causes a decrease in the neuron-supporting ability, these findings further suggests that the gain of function of TDP-43 may cause neurotoxicity by inducing cell cycle arrest and death in glial cells.

Original languageEnglish
Pages (from-to)271-276
Number of pages6
JournalNeuroscience Letters
Volume506
Issue number2
DOIs
Publication statusPublished - 2012 Jan 11
Externally publishedYes

Keywords

  • ALS
  • Cell cycle
  • FTLD-U
  • Non-neuron-autonomous toxicity
  • P53
  • TDP-43

ASJC Scopus subject areas

  • Neuroscience(all)

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