Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Proc Natl Acad Sci U S A. 2016 Mar 29;113(13):3428-35. doi: 10.1073/pnas.1519473113. Epub 2016 Feb 29.


Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.

Keywords: dopaminergic neuron; ferroportin; iron; neurodegeneration; transferrin receptor.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Cation Transport Proteins / deficiency
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Dopaminergic Neurons / metabolism*
  • Dopaminergic Neurons / pathology
  • Female
  • Homeostasis
  • Iron / metabolism*
  • Male
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Degeneration / etiology*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / pathology
  • Receptors, Transferrin / deficiency
  • Receptors, Transferrin / genetics
  • Receptors, Transferrin / metabolism


  • Cation Transport Proteins
  • Receptors, Transferrin
  • Tfrc protein, mouse
  • metal transporting protein 1
  • Iron