Dysregulation of iron homeostasis in the CNS contributes to disease progression in a mouse model of amyotrophic lateral sclerosis

Young Jeong Suh, Khizr I. Rathore, Katrin Schulz, Prem Ponka, Paolo Arosio, Samuel David

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Amyotrophic lateral sclerosis (ALS), characterized by degeneration of spinal motor neurons, consists of sporadic and familial forms. One cause of familial ALS is missense mutations in the superoxide dismutase 1 (SOD1) gene. Iron accumulation occurs in the CNS of both forms of ALS; however, its contribution to the pathogenesis of ALS is not known. We examined the role of iron in a transgenic mouse line overexpressing the human SOD1G37R mutant. We show that multiple mechanisms may underlie the iron accumulation in neurons and glia in SOD1G37R transgenic mice. These include dysregulation of proteins involved in iron influx and sensing of intracellular iron; iron accumulation in ventral motor neurons secondary to blockage of anterograde axonal transport; and increased mitochondrial iron load in neurons and glia. We also show that treatment of SOD1G37R mice with an iron chelator extends life span by 5 weeks, accompanied by increased survival of spinal motor neurons and improved locomotor function. These data suggest that iron chelator therapy might be useful for the treatment of ALS.

Original languageEnglish (US)
Pages (from-to)610-619
Number of pages10
JournalJournal of Neuroscience
Volume29
Issue number3
DOIs
StatePublished - Jan 21 2009
Externally publishedYes

Keywords

  • ALS
  • Free radicals
  • Iron
  • Neurodegeneration
  • Neuron death
  • Spinal cord

ASJC Scopus subject areas

  • Neuroscience(all)

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