Iron and neurodegeneration: from cellular homeostasis to disease

Abstract

Accumulation of iron (Fe) is often detected in the brains of people suffering from neurodegenerative diseases. High Fe concentrations have been consistently observed in Parkinson's, Alzheimer's, and Huntington's diseases; however, it is not clear whether this Fe contributes to the progression of these diseases. Other conditions, such as Friedreich's ataxia or neuroferritinopathy are associated with genetic factors that cause Fe misregulation. Consequently, excessive intracellular Fe increases oxidative stress, which leads to neuronal dysfunction and death. The characterization of the mechanisms involved in the misregulation of Fe in the brain is crucial to understand the pathology of the neurodegenerative disorders and develop new therapeutic strategies. Saccharomyces cerevisiae, as the best understood eukaryotic organism, has already begun to play a role in the neurological disorders; thus it could perhaps become a valuable tool also to study the metalloneurobiology.

Figure 1

The brain iron homeostasis. Iron (Fe) binds to transferrin (Tf), enters the brain through the transferrin receptors (TfR) by endocytosis, and translocates across the endosomal membrane through the divalent metal transporter 1 (DMT1). Lactoferrin receptors (LfR) provide another pathway to transport Fe from Fe containing lactoferrin across the cell membranes. Inside the cell Fe binds to H-ferritin and accumulates around the neuromelanin. Ferroportin (Fpn) transports Fe²⁺ outside the neuron that is oxidized to Fe³⁺ by ceruloplasmin promoting its binding to Tf.