Study: Protecting Neurons in Parkinson's Disease
Researchers in the Center for Neural Science and Medicine at Cedars-Sinai have demonstrated that increasing the production of a neurotransmitter called norepinephrine in the brain could potentially help prevent motor dysfunction in people with Parkinson's disease. Their study, conducted in mice, was published in the peer-reviewed journal PLOS One.
Nearly 1 million people in the U.S. have Parkinson's disease, a disorder of the central nervous system that causes tremors, stiffness, slowing of movement and poor balance that worsens over time. These motor symptoms are caused by low or falling levels of dopamine, a neurotransmitter that helps coordinate body movements, among other functions.
Parkinson's disease also causes nonmotor symptoms such as sleep disturbance, bowel and bladder problems, digestive issues, and problems with the skin, heart rate, and blood pressure. Previous research has connected these symptoms with another neurotransmitter called norepinephrine, which is important in the body's fight-or-flight response to stress.
Both of these signaling molecules, which allow nerve cells to communicate with each other, are produced in the adrenal glands at the top of the kidneys and in distinct regions in the brain. The death of dopamine-producing neurons in the brain's substantia nigra region has been established as a key trigger for the onset of motor dysfunction in patients with Parkinson's disease.
The role that norepinephrine, which is produced in the locus coeruleus region of the brain, plays in Parkinson's disease has been less well understood.
Celine E. Riera, PhD
"Norepinephrine is a very interesting molecule," said Celine Riera, PhD, a research scientist in the Cedars-Sinai Board of Governors Regenerative Medicine Institute and senior author of the study. "We understand its role in the peripheral nervous system but wanted to find a way to learn more about its role in the brains of patients with Parkinson's disease."
In the peripheral nervous system—the nerves that relay information between the brain and the rest of the body—norepinephrine increases heart rate and blood pressure in response to stress. In people with Parkinson's disease, high levels of norepinephrine in the peripheral nervous system have been linked with heart disease and diabetes, Riera said.
Previous research by Michele Tagliati, MD, director of the Movement Disorders Clinic at Cedars-Sinai, the Caron and Steven D. Broidy Chair in Movement Disorders, and a co-author of the study, found that diabetes and insulin resistance may further aggravate the progression of Parkinson's disease.
To more fully explore the role of norepinephrine in the brain, Riera and her team—which includes Predrag Jovanovic, PhD, a postdoctoral fellow and first author of the study—worked with laboratory mice that were genetically modified to develop Parkinson's disease.
"By around the time the mice are 9 months of age, we expect that dopamine-producing neurons in the brains of these mice will begin to die, causing motor coordination problems, and that the mice themselves will die quite soon after symptoms develop," Jovanovic said.
Before their mice developed symptoms, the investigators administered medications to continuously stimulate norepinephrine production in their brains for six weeks.
"Based on the fact that norepinephrine is detrimental in the peripheral nervous system in people with Parkinson's disease, we expected to see a detrimental effect in the central nervous system of the mice, as well," Riera said. "But we didn't."
In fact, the norepinephrine-producing neurons in the locus coeruleus physically connected via axon nerve fibers to dopamine-producing neurons in the substantia nigra.
"In these mice, connection with the norepinephrine-producing neurons in the locus coeruleus seemed to protect the dopaminergic neurons," Riera said. "The neurons looked much healthier than expected, and the mice did not develop motor deficits."
These results point to the importance of non-motor symptoms in Parkinson's disease, Riera said.
There's a theory that perhaps Parkinson's disease progresses from the locus coeruleus, where norepinephrine is produced, to the substantia nigra, where dopamine is produced, and our study supports that theory, Riera said.
"Many patients with Parkinson's disease experience sleep problems, olfactory problems and constipation, and the locus coeruleus is a key player in controlling these functions," Riera said. "These non-motor symptoms don't get as much attention as the motor symptoms, but they may tell us a lot about what is going on in the brain. And figuring out what is going on in the brain is the key to treating the disease."