30 March 2003. A large, collaborative group led by Julie Andersen at the Buck Institute for Research in Aging, Novato, California, demonstrates that lowering the bioavailability of iron-both systemically and in dopaminergic neurons-protects mice against chemically induced Parkinson's disease (PD). Published in the March 27 Neuron, this work supports previous studies implicating the metal in the etiology of PD.
First author Deepinder Kaur and colleagues used two approaches to reduce the amount of iron available to neurons in the substantia nigra (SN), the part of the brain most affected by PD. First, the authors made transgenic mice which express large amounts of the iron storage protein ferritin in dopaminergic neurons of the SN; ferritin is a magnet for iron, sequestering upwards of 4,500 molecules of the atom per protein. When Kaur and colleagues exposed these mice to the chemical MPTP, which induces Parkinson's-like neurodegeneration, the animals were protected. In contrast to wild-type mice, which lose about 30 percent of SN dopaminergic neurons in response to MPTP, there were no significant losses of neurons in the transgenic mice. Second, Kaur et al. used the iron chelator clioquinol to achieve a systemic reduction in reactive iron. Clioquinol reduced the amount of free iron in the substantia nigra by about 30 percent, and also prevented loss of dopaminergic neurons in response to MPTP. Furthermore, in both clioquinol-treated and transgenic animals, MPTP-associated loss of motor activity was attenuated by 30 and 60 percent, respectively.
Iron is thought to mediate oxidative damage by catalyzing the conversion of superoxide-a reactive form of oxygen formed during normal respiration-to the hydroxyl radical. The latter is even more reactive, making and breaking bonds in proteins that can render them inactive. By measuring such protein oxidation, Kaur and colleagues show that clioquinol prevents MPTP-induced oxidative stress.
The chelator has also shown promise for treatment for other neurodegenerative diseases. Ashley Bush at Massachusetts General Hospital in Charlestown and colleagues recently showed that it can reduce amyloid burden in mouse models of Alzheimer's disease (see ARF related news story), probably by virtue of its ability also to chelate copper and zinc atoms, which contribute to formation of amyloid-β plaques (see ARF related news story). A phase 2 trial has been completed in Australia to assess its usefulness for human AD (Masters, 2002). However, as Greg Cole of the University of California in Los Angeles points out in an accompanying preview article, results from the trial are still being analyzed. The drug is not without its drawbacks, having been removed from the market after linkage to thousands of cases of subacute myeloneuropathy in Japan. Nevertheless, Kaur et al. find no toxic effect in mice, suggesting that, at least for the doses required to ameliorate symptoms of Parkinson's disease, clioquinol may prove safe and effective.
Meanwhile, Shawn Burdette and Stephen Lippard from MIT draw attention to molecular advances and future directions of what they term "metalloneurochemistry," the study of metal ions in the brain and nervous system. There are major advances to be made at the intersection of bioinorganic chemistry and neurobiology, they remind us. Zinc, for example, is bound by a variety of proteins, including metallothioneins and membrane-bound transporters, which may play important roles in neurodegenerative diseases. For example, Lee et al. recently reported that ablating a version of the zinc transporter reduces the formation of amyloid plaques in transgenic mice expressing human AβPP (see ARF related news story); in Alzheimer's patients, levels of the protein metallothionein III, which has multiple zinc binding sites, are reduced.
Burdette and Lippard also discuss the role of the other metals and advances in development of fluorescent metal sensors. They call on bioinorganic chemists to enter this area of research to make new inroads into neurodegeneration. Their review appears in the March 24 PNAS early online edition.-Tom Fagan.
Kaur D, Yantiri F, Rajagopalan S, Kumar J, Mo JQ, Boonplueang R, Viswanath V, Jacobs R, Yang L, Beal MF, DiMonte D, Volitaskis I, Ellerby L, Cherny RA, Bush AI, Andersen JK. Genetics or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease. Neuron. 2003 Mar 27;37:923-933. Abstract
Cole GM. Ironic fate: can a banned drug control metal heavies in neurodegenerative diseases? Neuron. 2003 Mar 27;37:890-891. Abstract
Burdette SC, Lippard SJ. Bioinorganic Chemistry Special Feature: Meeting of the minds: Metalloneurochemistry. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):3605-10. Abstract