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Richard Smeyne, PhD, gets the same reaction every time he gives a tour of his laboratory. Visitors tilt their heads, furl their brows and ask the obvious question: “Why would the world’s premier center for the research and treatment of childhood illnesses be studying Parkinson’s disease?”
Smeyne draws his answer from the U.S. space program — the “Tang effect” (yes, the orange powder drink mix).
“We spent millions of dollars to go to the moon, and the things that came out of it for the general public include Tang, ear thermometers and smoke detectors,” he explains. “In that same vein, while our mission is to treat children, our research goals are to study basic developmental mechanisms that aren’t necessarily limited to childhood cancer. So while we hope to find the underlying basis of Parkinson’s disease, this research may also have applications for the children we treat.”
Smeyne and his colleagues in St. Jude Developmental Neurobiology are searching for the exact location of genes that could be used to screen people at risk for Parkinson’s disease. St. Jude is home to one of a handful of programs in the world taking a serious look at the benefits exercise could have on curbing the disease’s symptoms and progression. The findings could offer clues to a variety of neurodegenerative diseases, as well as pediatric and adult brain tumors.
Parkinson’s disease can turn even the simple act of waving a hand into a battle between the brain and the nerves. The progressive disease afflicts 1 million Americans and 2 percent of all people older than 55, making it the third most common neurological disease after Alzheimer’s and a form of dementia. Many people recognize Parkinson’s characteristic symptoms — tremors and the loss of balance and coordination — from seeing celebrities like Michael J. Fox, Pope John Paul II, Janet Reno and Muhammad Ali cope with the disease.
Although it exacts a hefty physical toll on its victims, Parkinson’s disease rarely affects the intellect.
“This is a disease where in most cases, your mental faculties don’t deteriorate, but you physically become immobile,” Smeyne says. “In the end stages, it’s like being trapped in your own body.”
The trap is set when nerve cells, or neurons, in a portion of the brain called the substantia nigra are damaged or destroyed. As a result, the cells can no longer release dopamine, a chemical that helps keep muscle movement smooth and controlled. The symptoms of Parkinson’s disease appear when most neurons in the substantia nigra die.
“Until 70 percent of these cells are dead, you don’t get one symptom,” Smeyne says. “But the bad part is that once you get the disease, those neurons cannot be rescued. You can’t turn them back on or get them to work better. They’re gone for good.”
Smeyne is trying to figure out why this happens and, specifically, how to predict who will succumb to the disease. While the cause of Parkinson’s disease is largely unknown, Smeyne thinks it is most likely due to a genetic susceptibility to environmental agents such as certain pesticides and other toxins. The current gold standard in treatment is the drug levodopa, or L-dopa, which neurons can convert into dopamine to replenish the brain’s dwindling supply. Although the drug is remarkable at stopping Parkinson’s symptoms, it isn’t a permanent cure.
“It wears off,” Smeyne says. “Eventually it doesn’t work anymore, and the cells even regulate against it. Also, some people think — and we’re among them — that giving L-dopa actually causes the disease to progress faster.”
Gaining a better understanding of how the brain cells work could lead to earlier detection and more effective treatment.
Because Parkinson’s symptoms appear late — sometimes several years after onset — and are often coupled with other illnesses of aging, understanding the disease’s basic cell biology was limited until an accidental discovery 22 years ago. That’s when a group of California drug users botched an attempt to make synthetic heroin and instead produced a neurotoxin known as MPTP. The next day, the addicts were catatonic with severe Parkinsonian symptoms. All of the patients improved immediately with L-dopa.
Since then, MPTP has opened the doors for researchers to create lab models to study Parkinson’s disease. Now Smeyne’s lab is homing in on the genes that can lead individuals to develop Parkinson’s disease.
“We’ve actually shown in our lab that the nerve cells die only after they interact with another type of cell in the brain called a glial cell,” Smeyne says. Glial cells make up the brain’s support tissue and do not conduct electrical impulses as do neurons. While popular belief holds that glial cells are the glue that holds neurons together, Smeyne takes another view.
“We believe that glia do not only support neurons, but play a much more critical role in brain function,” he says. “I believe that Parkinson’s disease will ultimately be found to be a disease of glial cells that affect neurons through their interactions.”
Smeyne’s lab is now testing ways to interfere with the process and keep cell death under 70 percent. “If we do that, we will stop the symptoms from ever arising, which is an effective cure in itself,” Smeyne says.
Besides L-dopa and other drugs, current Parkinson treatments range from stem cell transplantation to deep brain stimulation, where a pacemaker conducts impulses to electrodes surgically inserted in the brain.
“Right now, there’s a huge emphasis in biotech and pharmaceutical companies on using compounds called neurotrophins, or growth factors, as therapies because it’s been shown that those chemicals protect the neurons that die in Parkinson’s disease,” Smeyne says. “The problem is with the delivery of these compounds into the brain; there is very little control. So my lab is looking for ways to stop the process without using these drugs.”
Aerobic exercise may be the key. The simple act of running increases neurotrophin levels in the brain. The increased levels support neurons damaged by MPTP and helps them to recover. Now, Smeyne is studying how much exercise is needed and how long the neuron protection lasts.
St. Jude researchers think the findings may be useful for children who undergo cancer therapy. Studies have shown that about four years after receiving full cranial radiation, some children experience a decrease in their IQ levels. The cause is unknown, but neuron loss could be one reason, says Smeyne.
Putting the “Tang effect” into practice, St. Jude scientists are discussing a research project to see if exercise can help reduce nerve cell death in these children. “This research that came out of Parkinson’s disease may work well with handling some of the secondary effects that we see from chemotherapy and radiation,” Smeyne says. “This is the kind of thing that can only happen at St. Jude, where our research can be translated to the clinic almost seamlessly.”
Reprinted from summer 2004 Promise magazine.
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