Sci. Aging Knowl. Environ., 26 March 2003
Vol. 2003, Issue 12, p. nw48
[DOI: 10.1126/sageke.2003.12.nw48]


Turn Off the Iron

Impounding the metal might thwart Parkinson's disease progression

Kate Ramsayer;2003/12/nw48

Key Words: chelation • ferrous • ferric

Iron might smooth the way for neurodegeneration in Parkinson's disease (PD), according to new work. The study reveals that the metal doesn't just accumulate during the disease but also promotes it. Mice with improved iron-sequestering capacities--due to genetic alterations or drug treatment--preserve the neurons affected in PD; these results suggest new therapeutic strategies for reining in the illness.

PD patients lose the dark-colored, dopamine-filled neurons of the substantia nigra, the brain region that regulates movement. In those with the disease, this area also contains elevated amounts of iron. Substantia nigra neurons require iron to synthesize dopamine, a chemical that transmits nerve signals, but the metal can also react with dopamine breakdown products to generate harmful agents called reactive oxygen species (ROS) (see "The Two Faces of Oxygen"). Researchers haven't yet clarified iron's role in PD. "No one knew whether [iron] was something that was causative for the disease or a sign of trauma due to the disease itself," says neuroscientist Julie Andersen of the Buck Institute for Age Research in Novato, California.

To probe that issue, Andersen and colleagues tested whether depleting iron in the brain protected rodents against a neurotoxin called MPTP, which instigates Parkinson-like symptoms. The researchers engineered mice to pump up the substantia nigra's production of ferritin, a molecule that captures the reactive form of iron and stores it in a benign state. They then injected the animals with MPTP and analyzed tissue from the substantia nigra. In normal mice treated with the compound, ROS concentrations increased, dopamine quantities fell, and neurons perished. However, when mice with extra ferritin received MPTP, the number of living neurons and the amounts of ROS and dopamine remained almost the same as in untreated animals. In addition, rodents with boosted ferritin doses had better balance than their normal counterparts did. These findings suggest that iron helps spur the Parkinson-like effects of MPTP.

To extend the results, the researchers treated normal mice with clioquinol, a compound that seizes metals and has shown promise in delaying progression of Alzheimer's disease in a small clinical study (see "Mindful of Metal"). Clioquinol protected the animals from the harmful effects of MPTP, although not to the degree that extra ferritin did. Next, the scientists want to test clioquinol in other models of PD, because the effects of MPTP don't perfectly mimic the disease, says neuroscientist and co-author Ashley Bush of Harvard Medical School in Boston, Massachusetts. Those and other studies should clarify whether iron triggers PD through its ROS-generating capacity.

These experiments "suggest that iron may be critical for the development or progression of Parkinson's disease," says Lennart Mucke of the University of California, San Francisco. "The study demonstrates convincingly that removing iron can protect the brain against MPTP-induced neurodegeneration." Depending on how closely MPTP-induced symptoms simulate those of PD, blocking iron using drugs such as clioquinol "might be a way of preventing deterioration [due to] the disease," he says. Whether the results will lead to new treatments remains uncertain, but the study steels the role of iron in PD.

--Kate Ramsayer

March 26, 2003
  1. D. Kaur et al., Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron 37, 899-909 (2003). [Abstract] [Full Text] [CrossRef][Medline]
Citation: K. Ramsayer, Turn Off the Iron. Sci. SAGE KE 2003, nw48 (26 March 2003);2003/12/nw48

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