Battling Parkinson's on Two Fronts

Dopamine is a jack-of-all-trades. In the brain, it’s a neural-signal transmitter that plays a central role in a range of functions including arousal, motivation, and cognition. Dopamine also is involved with motor control, and low levels of the chemical are responsible for the motor-control impairment characteristic of neurodegenerative diseases such as Parkinson’s.

In separate preclinical projects, Emory researchers Gary Miller and Malu Tansey are exploring new ways to optimize dopamine levels that may improve treatment for Parkinson’s and other diseases
of the central nervous system.

When a cell produces dopamine, it is stored in small packages, or vesicles, by a protein called the vesicular monoamine transporter (VMAT 2), according to Miller, professor and associate dean for research at Emory’s Rollins School of Public Health. Dopamine is released, finds its receptor, and then is brought back to the cell for reuse.

“Dopamine gets used thousands and thousands of times, but it can be reused only if it is packaged correctly by the VMAT 2,” Miller explains. “If the process is disrupted and the dopamine is not stored correctly, or if it’s leaking out into other parts of the cell, it can cause Parkinson’s-like degeneration problems. Dopamine needs to be stored at the right place in order for it to do its job.”

Rather than looking at ways to increase the amount of dopamine in the brain, Miller’s approach focuses on the packaging side of the process. “It’s all about increasing the efficiency of the system,” he says of his research.

Miller’s team worked with transgenic mice with increased VMAT 2 levels and found a corresponding increase in dopamine release along with increased movement. The researchers also noted improved outcomes in terms of anxiety and depressive behaviors, as well as protection from MPTP, a chemical that can cause Parkinson’s-related damage in the brain.

“Now the idea is to see if we can improve the storage of dopamine pharmaceutically,” says Miller.

Therapeutic enhancement of VMAT 2 might also be conducted in tandem with L-dopa, the current drug of choice for treating Parkinson’s. A metabolic precursor of dopamine, L-dopa increases the amount of dopamine in the brain, but it carries serious side effects—muscle spasms, abnormal heart rhythms, and gastrointestinal problems, among others—and its effectiveness diminishes over time. 

“If you can enhance the storage of the dopamine that comes from L-dopa, if nothing else, you could take less of the drug,” Miller notes. “And anytime you take less of a drug, you tend to decrease the side effects.”

The research indicates that sustainable, improved VMAT 2, function also could help treat a variety of central nervous system disorders that involve the storage and release of chemicals besides dopamine, including serotonin and norepinephrine.

Miller’s study was published in the June 17, 2014, edition of Proceedings of the National Academy of Sciences.

Another aspect of the motor-control impairment associated with Parkinson’s is the loss of dopamine-producing neurons due to chronic inflammation, according to Tansey, associate professor of physiology at the School of Medicine. 

For reasons not yet fully understood, these nerve cells appear to be susceptible to damage and death by soluble tumor necrosis factor (TNF), an inflammatory molecule. 

With support from the Michael J. Fox Foundation, Tansey and her research group are investigating an experimental anti-inflammatory drug, XPro1595, that may significantly slow the advance of Parkinson’s symptoms by neutralizing the damaging effects of soluble TNF on dopamine-producing neurons.

“You’ll lose some dopamine-producing neurons just in the aging process, since inflammation goes up as you get older,” she explains. “Certain neurons in the brain handle inflammatory stress less well than others, so it’s possible that as you age, the inflammation in certain parts of the brain becomes too much to handle, perhaps because of external factors that are known risks for the development of Parkinson’s. And if you lose, say, 70 percent of your dopamine-producing neurons, that’s thought to be close to the threshold where you start experiencing the motor symptoms that would allow a neurologist to do a clinical diagnosis of Parkinson’s disease.”

Using a model of Parkinson’s in rats, the researchers found that an injection of XPro given shortly after symptoms appeared resulted in only a 15 percent loss in dopamine-producing neurons, versus a 55 percent loss in the control group. Motor-skill impairment was reduced accordingly.

However, when the injection was delayed, neuron loss rose to 44 percent, suggesting that XPro’s effectiveness may depend on early intervention.

“Recent clinical studies indicate there is a four- or five-year window between diagnosis of Parkinson’s disease and the time when the maximum number of vulnerable neurons are lost,” Tansey notes. “If this is true, and if inflammation is playing a key role during this window, then we might be able to slow or halt the progression of Parkinson’s with a treatment like XPro1595.”

Tansey estimates that the drug, injected under the skin, could delay the disease’s advance by ten or perhaps even twenty years.

Another key advantage of XPro is that it’s specific only to soluble TNF, she says. Anti-inflammatory drugs on the market don’t discriminate between soluble TNF and another form of the molecule, membrane-bound TNF. The latter protects against infection and promotes the health of the myelin sheath that facilitates the transmission of nerve signals. So while current drugs neutralize soluble TNF, they also disable the beneficial TNF, leading to a higher risk of infection and other unwanted side effects.

“We think this will be the right drug for chronic inflammatory neurological diseases, not only because it spares the membrane-bound TNF, but also because it can get into the brain and do its work there, whereas the molecules of other drugs are too large to get into the brain,” Tansey says.

Her next step is to test XPro in a nonhuman primate model of Parkinson’s.

The results of her research were published in the July 24, 2014, edition of the Journal of Parkinson’s Disease.