Nematodes provide clues to dopamine's role in human aging diseases

Research carried out with a paintbrush bristle, a metronome, smelly chemicals and thousands of microscopic worms called nematodes may reveal important information about human aging diseases like Parkinson's and Alzheimer's, thanks to a grant from the Ellison Medical Foundation awarded to a University at Buffalo neurobiologist.

Denise M. Ferkey, Ph.D., assistant professor of biological sciences in UB's College of Arts and Sciences, has received a prestigious $200,000 New Scholar Award in Aging from the Ellison Medical Foundation in order to investigate the little-understood link between the neurotransmitter called dopamine and diseases like Parkinson's and Alzheimer's.

The New Scholar Awards reward exceptional scientists during the first three years of their research careers. The Ellison Medical Foundation awarded just 18 of these awards this year nationwide.

The purpose of Ferkey's grant is to look at how dopamine affects the complex chain of messages that constitutes neuronal signaling, ultimately affecting mental and physical health, especially in aging adults.

Her research addresses fundamental questions about how dopamine affects neuronal signal transduction using as a model the chemosensation (ability to smell and taste) of the nematode C. elegans, found in backyards everywhere.

The ultimate goal of the research is to discover new signaling molecules and pathways that are targets of dopamine in order to identify new avenues for drug development for human neurological age-related diseases.

"We know that Parkinson's disease results from the progressive loss of the dopamine-producing neurons in the brain," Ferkey said, "but we don't yet fully understand what dopamine does normally to affect neuronal signaling. It is absolutely critical to understand the normal role of dopamine before we can begin to understand how loss of dopamine contributes to human diseases."

Her research takes a novel approach by using chemosensory responses, the behaviors that organisms exhibit when they encounter chemical sensory stimuli, as a marker for dopamine function in vivo.

In her previous position as a postdoctoral researcher at Massachusetts General Hospital and Harvard Medical School, Ferkey found that dopamine affects the ways in which C. elegans respond to their environments.

In her current work at UB, she builds on that observation by using C. elegans as a model to dissect dopamine function in individual cells and in neuronal circuits in the whole living animal.

Nematodes, or worms, are pretty easy to "read," according to Ferkey, relying primarily on their ability to taste and smell to find mates and food and avoid harm.

"If a neuron in a circuit is firing correctly, we see a behavioral response," she said.

She noted that with just 302 neurons compared to a human brain's 100 billion neurons, the nervous system of a C. elegans is far simpler, naturally, than that of a human.

"However, it's amazing that the chemicals that stimulate our brains are the same ones that function in the C. elegans' nervous system," she said. "That's why it's not strange to say that by understanding their neurons and how they function, they will hopefully give us new insights into complex human diseases."

In the lab, Ferkey and her students provoke a response by presenting an individual nematode with a single paint brush hair that has been attached to the end of a pipette and dipped in an "odorous" chemical.

If the nematode senses a chemical that's potentially toxic the researchers, observing the organisms under a dissecting microscope, will see it instinctively back away within two seconds, while the lab's metronome ticks away.

Those avoidance responses, repeated thousands of times in the lab, will enable Ferkey and her colleagues to determine which neurons in a circuit dopamine acts upon and how dopamine ultimately affects the sensitivity of those neurons.

"Recent studies suggest that dopamine has novel targets in the nervous system that have not yet been identified," said Ferkey.

Thus, her research also will focus on developing a genetic screen that may reveal new physiological targets of dopamine in neuronal circuits in living animals.

Such a genetic screen will be of special interest, she added, because current dopamine treatments for Parkinson's disease decrease in efficacy as a patient's disease progresses.

By providing detailed information on as yet unknown dopamine receptors and pathways, it is hoped that Ferkey's research at UB will provide potential new targets for drug development and therapy for human diseases that result from decreased dopamine signaling.