Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice

Significance The brain requires iron for mitochondrial respiration and synthesis of myelin, neurotransmitters, and monoamine oxidases. Iron accumulates in distinct parts of the brain in patients with neurodegenerative diseases, and some have proposed that neurons die because they contain too much iron. Neuronal iron handling is not well understood. We focused on dopaminergic neurons, affected in Parkinson’s disease, and manipulated molecules involve in iron uptake and release. We showed that loss of ferroportin, which exports cellular iron, had no apparent effect. In contrast, loss of transferrin receptor, involved in iron uptake, caused neuronal iron deficiency and neurodegeneration with features similar to Parkinson’s disease. We propose that neuronal iron deficiency may contribute to neurodegeneration in human disease. 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.