Gary Miller's mice have Parkinson's. Can he cure them?
Gary Miller’s mice—genetically engineered to have flaws in the packaging, storage, and transport of dopamine—are providing essential clues about how Parkinson’s disease (PD) develops and how environmental toxins can cause or speed up that process.
By Sylvia Wrobel
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It’s a question made to order for Miller, a neurotoxicologist who leads an interdisciplinary Parkinson’s disease research and treatment center based in the RSPH. Soon, working in one of the school’s new wet laboratories, he will use his unique mouse model of PD to develop biomarkers of exposure, risk, and early disease and to test whether a novel therapeutic agent can restore function to a damaged dopamine system.
More than for any other neurodegenerative disease, a growing amount of cellular and population evidence points to a connection between Parkinson’s and exposure to environmental toxins. A recent Harvard study found a 75% increased risk of PD in those who reported exposure to pesticides, and Miller has shown that certain classes of pesticides induce Parkinson’s-like damage in the brains of mice.
A nationally recognized expert in the impact of toxins on PD, Miller doesn’t lay all the blame for PD on toxins. The majority of cases, he says, probably result from a combination of factors. A person with genetic risks might develop PD at age 70, even without exposure to toxins (or other insults like head trauma), but exposure to toxins may speed up onset by 10 or more years.
What Miller seeks to understand is the mechanism through which this happens. His genetically engineered mice are proving to be a potent research tool. PD occurs when the brain cells that produce the neurotransmitter dopamine begin to waste away, for reasons unknown. Without sufficient dopamine, the nerve cells cannot properly send messages, leading to loss of muscle function.
The process is slow and silent, sometimes extending over decades. Some of the early manifestations of PD, like loss of olfactory function or depression, are only now being recognized. By the time the motion disturbances for which PD is best known—tremor, halting movements, rigidity, loss of balance—show up, 70% to 80% of the dopamine-producing cells may already be dead. Untreated, the disorder gets worse until a person is totally disabled. For some patients, PD leads to a deterioration of all brain functions and early death. There is no cure. What are needed are biomarkers of exposure and disease progression and a treatment to counteract the disease process and restore function to the dopamine-producing system. That’s where Miller’s mice come in.
Of mice and dopamine
Miller knows mice. He began using PD mouse models while a postdoctoral fellow at Emory, working with neurology chair Allan Levey in the School of Medicine. Continuing his postdoctoral studies at Duke, Miller was part of a team that used genetic engineering to completely knock out genes related to dopamine function. He was hooked on the concept that manipulating genes in mice could provide answers to the disease that had afflicted his own grandfather.
Today, Miller serves as professor of environmental and occupational health and associate dean for research at Rollins. Since 2008, he has directed the multidisciplinary Emory Parkinson’s Disease Collaborative Environmental Research Center. He applied for and won five years of NIH funding for the center to study how (and which) chemical toxins cause neuron death leading to PD and to identify genes that increase susceptibility or resistance to the PD-inducing effects of toxins. The unique mouse model created by Miller would come to play a starring role in the center, with research involving scientists from other disciplines in and outside of the RSPH.
Dopamine has always been a double-edged sword, says Miller. The brain has to have it, but it is toxic if not in the right place. He created a new PD animal model to see what happens when the storage and handling of dopamine are disrupted. Miller’s mice have been genetically altered so they (and their offspring) produce abnormally low amounts of VMAT (vesicular monoamine transporter), a protein that packages neurotransmitters such as dopamine into little sacs called vesicles and transports them out of brain cells. The VMAT gene in mice is 92% identical to its counterpart in humans.
The lack of sufficient VMAT, and the subsequent failure to properly transport dopamine out of the cells, creates oxidative stress and damage to the same brain cells as those that die in human PD. It also causes the onset of PD symptoms—and not just the familiar problems with motion.
Parkinson’s before the tremor
Other scientists have created PD mouse models by chemically damaging brain cells, but that can inadvertently cause widespread damage and produce mice with a variety of ailments and problems, clouding the issue of what is related to PD. Miller’s VMAT mice have normal vision, sense of touch, and muscle strength, functions typically normal in human PD patients. That means they have the capacity to perform various tests, such as finding their way around mazes, and their symptoms are all related to PD.
Miller’s mice are the first PD animal model to demonstrate both the motor symptoms and the non-motor symptoms of PD—the latter a particular focus of attention over the past decade. By the time the PD mice are two months old, they no longer discriminate well among scents, an important part of mouse life lost. At a year—middle age for mice—they fall asleep more quickly than normal; have delayed emptying of the stomach, which in humans can cause pain, heartburn, and distension; and display anxiety and behaviors associated with depression (giving up easily, for example) and mood disorders that respond to antidepressant drugs. Next, PD-like motor problems develop, becoming more profound as the mice age.
Miller and his team have published extensively regarding the neurodegeneration caused by faulty handling of dopamine in the part of the brain associated with motor symptoms. But VMAT also packages and transports other neurotransmitters, including norepinephrine and serotonin, which regulate mood as well as some physiological functions. Last year, Tonya Taylor, a graduate student in Miller’s lab (and a recent recipient of a National Research Service Award from the National Institute of Environmental Health Sciences) was first author of a paper from the lab describing how a diminishment in VMAT causes faulty handling of these other transmitters, causing non-motor problems in the PD mice. Since L-dopa, the most common PD treatment, does not help non-motor symptoms, Miller hopes the mice will help him identify medicines that do.
Miller found that some toxins, such as PCBs (polychlorinated biphenyls), inhibit actions of VMAT. He also found that exposure to toxins and genetically reduced VMAT produce identical brain changes. As he explores further how exposure may affect VMAT actions, he is focusing on the toxins themselves.
Some of the toxins that Miller has shown to be linked to risk for PD in mice and humans (including PCBs, dieldrin, and DDT) are officially gone, banned in the 1970s after being linked to cancer, but older patients still report exposures, and low levels still linger in the soil. Indeed, Miller has shown that PCB levels are higher in brain samples from people who died with PD than in those who died of other causes.
“We can’t ban all of the thousands of toxic products now on the market,” says Miller, citing the need to improve crop production and control insects. “But we can be careful.”
That’s why he has sorted out the chemical properties of various pesticides to determine which ones might pose the greatest risk and may require re-evaluation of policies and guidelines for use. Working with investigators in the School of Medicine, he also is developing metabolic biomarkers to identify people exposed to suspected pollutants and determine if this exposure contributes to disease onset and progression.
Protecting brain function
Although no one has yet found mutations in VMAT in people with PD, one group found that elevations in the protein appeared to protect against developing the disease. Now that Miller is close to understanding how VMAT deficiency causes PD and how altered VMAT may interact with exposure to toxins, he is looking for ways to intervene. He believes he knows how.
Earlier this year, Emory medical school investigators, led by pathologist Keqiang Ke, found a compound that protects brain cells against the kind of damage seen in seizure, stroke, and PD, achieving what so many other experimental “neuroprotective” drugs have failed to do over the past decade. The compound, 7,8-dihydroxyflavone, is a member of the flavonoid family of chemicals, abundant in fruits and vegetables. Because of its ability to cross the blood-brain barrier, its selective action on specific cells once it arrives in the brain, and the different pathway it uses to achieve its actions (mimicking one of the brain’s own growth factors), the investigators believe the compound could be the founder of a new class of brain-protecting drugs. When Miller gave it to mice that had been treated with a toxin that kills the same neurons as those affected by Parkinson’s, it prevented nearly all of the damage. More studies are under way, but Miller believes this novel therapeutic agent can restore ability to transport neurotransmitters both in animals genetically deficient in VMAT protein and in those exposed to neurotoxins.
Atlanta freelancer Sylvia Wrobel is a frequent contributor to Emory’s health sciences publications.
