Ferritin out iron's role

The amount of iron in the brain increases with normal ageing, but elevated iron levels are also associated with several neurodegenerative diseases, including Parkinson's disease. Reactive ferrous iron (Fe²⁺) can participate in the generation of cell-damaging free radicals, so it has been hypothesized that higher iron concentrations could play a part in the neuronal loss observed both in old age and, more drastically, in many diseases. However, as with many of the other observed biochemical and pathological changes that accompany neurodegenerative diseases, there is debate as to whether increasing iron levels themselves cause cellular damage, or are simply a consequence of damage caused by other factors. Convincing evidence for the detrimental effects of elevated iron in an acute animal model of Parkinson's disease is now presented in a study published in the March 27th issue of Neuron, in which Kaur et al. show that brain damage is diminished by reducing iron levels.

The authors used both transgenic and pharmacological methods to sequester iron in mice that were exposed to one or more doses of the neurotoxin MPTP, the standard method for producing animal models that mimic many of the signs of Parkinson's disease. In the transgenic approach, the heavy subunit of human ferritin was selectively expressed in dopaminergic neurons under the control of a tyrosine hydroxylase promoter. Ferritin converts harmful ferrous iron to unreactive ferric iron (Fe³⁺), which it sequesters in large quantities. The presence of ferritin greatly attenuated the loss of the vulnerable dopaminergic neurons in the substantia nigra, as assessed by stereological cell counts of tyrosine-hydroxylase-positive neurons seven days after MPTP administration. It also led to partial reverses in the increase in reactive oxygen species and decreases in glutathione levels seen after MPTP administration, changes which are also characteristic of Parkinson's disease brains.

A second iron-removing strategy — dosing with the metal chelating antibiotic 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) — was also shown to attenuate the MPTP-induced cell loss and detrimental biochemical changes. Clioquinol chelates both ferrous and ferric iron and is already in Phase II clinical trials for another neurodegenerative disease, Alzheimer's disease, in which its metal-chelating properties are thought to inhibit β-amyloid accumulation. In this study, clioquinol was shown to protect neurons after both acute and chronic (five day) MPTP insults. Both the ferritin-expressing and clioquinol-treated mice were reported to show less decline in motor activity than normal animals following dosing with MPTP.

With the identification of ferrous iron as a causative element in the pathological progression of Parkinson's disease, the search is on for agents that can achieve the delicate balance of sequestering excess reactive iron in vulnerable regions of the brain, without damaging the many systems that rely on normal iron levels for their functioning.