Science Editor

The longer that iron is exposed to the elements, the rustier it gets. In the mammalian body, rusty-ruddy hemoglobin gives blood its blood-red color. Just as environmental air and water conspire to hasten the rust process, their prime ingredient - oxygen - plays a double role in homeostasis.

Inhaled, O₂ fuels the heart that beats and the lungs that breathe. As a free radical, oxygen can act as a toxin, known as ROS - reactive oxygen species. Out in California two decades ago, a passel of slaphappy young heroin addicts unwittingly launched a neurotoxin that specifically caused Parkinson's disease (PD).

When they tried shooting up a new synthetic designer narcotic, the wannabe narcofreaks wound up injecting a vicious chemical called MPTP (methyl-phenyl-tetrahydro-pyridine). "It sent those addicts to the hospital, and some of them still have all the irreversible signs and symptoms of PD - muscle tremors, shuffling gait, rigid movements, droopy posture, mask-like facial expression."

So says neuromolecular biologist Julie Andersen, a professor at the Buck Institute for Age Research in Novato, Calif. "Those reckless, feckless victims built better than they knew, as the unintended consequence of their misfortune led to MPTP crafting relatively faithful animal models of parkinsonianism - the multiple symptoms of Parkinson disease." Andersen is a prime customer for putting MPTP to such PD-model use.

Novel Therapy For Parkinson's Disease

She is senior author of an article in the current issue of the semimonthly journal Neuron (an offshoot of Cell) dated March 27, 2003. Its title: "Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: A novel therapy for Parkinson's disease."

"The finding that comes with this paper," Andersen told BioWorld Today, "suggests that iron is a major player in the initiation of PD. Our paper in Neuron suggests that iron is involved in causing PD. That's very important therapeutically, because if we can bind iron up so that it can't precipitate in oxidative reactions, than this is a positive preventative therapeutic for the disease.

"Increase of iron in the parkinsonian brain," she continued, "is an idea that's been kicking around for a long time. But we used a chemical as specific as iron, namely increasing levels of ferritin. That's pretty definitive proof that iron is involved in the disease process itself. We proved this not only by expressing elevated levels of the iron-binding protein ferritin," Andersen went on, "but we also used the pharmacological agent clioquinol [CQ], which is an antibiotic. CQ is a metal chelator that's known to entrap other metals, including zinc and copper. That CQ was also efficacious in preventing parkinsonian symptoms in our animal model of the disease suggested that there may be pharmacological means by which this can be done in humans, rather than just genetic means.

"Ferritin is an iron-protein complex," Andersen explained, "that is the body's natural means of binding up iron in a form where it can't produce oxidative stress. Of course, iron is necessary for a lot of bodily functions, brain functions, but it's our idea that you want to have a homeostatic level of iron. You don't want it to be too low, because then it can't participate in processes such as DNA and RNA synthesis. But you don't want the iron to be too high because that can produce harmful oxidative stress. The ferritins are the major iron storage proteins in the body.

"If you're able to bind up high levels of iron," she went on, "and it prevents these Parkinson's symptoms in the animal model, it suggests that the iron participates in the neuropathology. That's an important component in causing the degeneration and loss of dopamine itself in the midbrain - which results in PD."

The Buck Institute's transgenic mice acquired the ferritin transgene. "We were interested in the concept that if we could bind up iron in such a way that it could not participate in oxidative reactions, this would prevent PD," Andersen said. "We wanted to express ferritin specifically within the dopamine-secreting neurons that are lost in PD. To target expression of ferritin to those neurons, we expressed that protein behind a promoter element, tyrosine hydroxylase [TH], which would express the protein only within catecholeminergic neurons, including those in the midbrain. So we hooked up the ferritin gene to an element of selective expression, not expressing it throughout the body or even throughout the brain. We wanted to look at targeted expression deep in the brain. So I think our in vivo experiments with those transgenic mice is an encouragement toward development of specific iron chelation agents that would act to bind up iron in the diseased brain."

On The Rotarod, Keep Your Footing!

Andersen and her co-authors relied on a classic device, the rotarod, to test the degree of PD symptomology in their transgenic mice. "It's a very widely used behavioral test to assess lost motor function. People with the disease lose the ability to initiate and sustain voluntary motor movement. We used the rotarod in order to test whether our treatments with genetic expression of ferritin, or the pharmacological CQ treatments, prevented the parkinsonian symptoms in this mouse model of PD.

"It's just a pencil-thick rod that rotates for a fairly simple task," Andersen explained. "We put a mouse on the rod and measured how long it remained on it before tumbling off. Our transgenic mice showed that they could maintain their voluntary motor events, but the treatment prevented or attenuated the MPTP-mediated loss in motor movement.

"The bulk of iron uptake into the brain occurs during the neonatal period in rodents - like two or three weeks postnatal. So we've been looking at the impact of neonatal iron feeding in rodents and how that impacts susceptibility to PD later in life.

"So what we're doing is feeding iron very early for a two-week period neonatally to 2 to 3 weeks of age, and seeing how that impacts susceptibility to PD in those animals, when they're kind of in late middle age - 12 to 16 months. This suggests that maybe we should begin paying attention to iron exposure very early on in the human life span. And that's important because many infant formulas contain elevated levels of iron. That's something," Andersen concluded, "we are investigating in our current studies."