Iron accumulation promotes TACE-mediated TNF-α secretion and neurodegeneration in a mouse model of ALS

Jae Keun Lee, Jin Hee Shin, Byoung Joo Gwag, Eui Ju Choi

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

Abstract

Oxidative stress contributes to degeneration of motor neurons in patients with amyotrophic lateral sclerosis (ALS) as well as transgenic mice overexpressing ALS-associated human superoxide dismutase 1 (SOD1) mutants. However, the molecular mechanism by which the ALS-linked SOD1 mutants including SOD1(G93A) induce oxidative stress remains unclear. Here, we show that iron was accumulated in ventral motor neurons from SOD1(G93A)-transgenic mice even at 4. weeks of age, subsequently inducing oxidative stress. Iron chelation with deferoxamine mesylate delayed disease onset and extended lifespan of SOD1(G93A) mice. Furthermore, SOD1(G93A)-induced iron accumulation mediated the increase in the enzymatic activity of TNF-α converting enzyme (TACE), leading to secretion of TNF-α at least in part through iron-dependent oxidative stress. Our findings suggest iron as a key determinant of early motor neuron degeneration as well as proinflammatory responses at symptomatic stage in SOD1(G93A) mice.

Original languageEnglish
Pages (from-to)63-69
Number of pages7
JournalNeurobiology of Disease
Volume80
DOIs
Publication statusPublished - 2015 Aug 1

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation Grant ( 2006-0093855 ) funded by the Ministry of Science, ICT & Future Planning of Korea, and by a Korea University grant (E.-J.C.). J.K.L was supported by the National Research Foundation Grant ( 2014R1A1A1002076 ) and by a Korea University grant. J.H.S was supported by the National Research Foundation Grant ( 2014R1A1A3052540 ).

Publisher Copyright:
© 2015 Elsevier Inc.

Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.

Keywords

  • ALS
  • Iron
  • Motor neuron death
  • TNF-α
  • TNF-α converting enzyme (TACE)

ASJC Scopus subject areas

  • Neurology

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