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

Neurobiol Dis. 2015 Aug:80:63-9. doi: 10.1016/j.nbd.2015.05.009. Epub 2015 May 20.


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.

Keywords: ALS; Iron; Motor neuron death; TNF-α; TNF-α converting enzyme (TACE).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism*
  • ADAM17 Protein
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism*
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Disease Models, Animal
  • Humans
  • Iron / metabolism
  • Iron / toxicity*
  • Mice
  • Mice, Transgenic
  • Motor Activity
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Oxidative Stress / genetics
  • Reactive Oxygen Species / metabolism
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Superoxide Dismutase / genetics*
  • Tumor Necrosis Factor-alpha / blood*


  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Iron
  • SOD1 G93A protein
  • Superoxide Dismutase
  • ADAM Proteins
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse