Finding a Brain Cell Fix

LEAH CHASE, Ph.D. | Associate Professor of Biology and Chemistry

About 2 percent of a person’s body weight is mostly responsible for the way the other 98 percent of it functions. The complex human brain, which usually weighs in at about three pounds, is the ultimate multi-tasker of human organs — processor of senses, memory and knowledge; coordinator of heartbeats, breaths and motor skills; releaser of hormones; regulator of metabolism; and more. Much more.

But malfunctions happen. Unfortunate abnormalities on a cellular level are the cause of a number of neurodegenerative diseases. These biological and chemical flaws, especially as they pertain to Parkinson’s disease, have driven Dr. Leah Chase’s neuroscience research agenda in Hope College’s Schaap Science Center for 15 years. Determining what mechanisms brain cells use to protect themselves, and how that information gets shared within the body, has made for busy lab operations and a first-time discovery for Chase and her student assistants.

Chase’s research has to do with cell oxidation. Every living cell needs oxygen, of course. But there’s a delicate balance; when oxidation in cells occurs at rapid, sudden or prolonged rates, the process can subject cells to stress.

Many scientists believe this oxidative stress may be at the root of Parkinson’s disease, especially in the brain’s basal ganglia, the primary processor for voluntary motor control (which Parkinson’s patients lose). The section of the basal ganglia where things go awry in Parkinson’s is called the substantia nigra. Its cells have high levels of dopamine, a neurotransmitter. When dopamine breaks down in those cells, oxidative stress goes up. Way up.

“Dopaminergic cells are inherently more susceptible to oxidative damage — and that’s why we think that oxidative stress is such an important component of the Parkinson’s disorder,” Chase explains.

Compounding the issue is the fact that the brain has the fastest-metabolizing cells in the human body (“because those cells are always working, working,” she clarifies). Metabolic processes cause oxidative stress, too.

The bottom line: Brain cells inherently need better protection from over-oxidation. That’s why we’ve been encouraged for decades to include more anti-oxidant-laden broccoli and blueberries in our diets.

Chase, however, wants to find out what human cells do naturally to protect themselves against oxidative stress. Grants from the National Science Foundation and Campbell Foundation have funded much of her research during Hope’s academic semesters and over a number of summers. She and her students have been conducting studies to scrutinize the naturally occurring antioxidant glutathione, its amino acid reagent cystine, and the molecular “pump” that regulates the two.

The team discovered an interesting phenomenon.

“When cells are in oxidative stress, they want more glutathione, but they can’t get that without getting more cystine,” Chase explains. Inside a cell, there’s a limited quantity. “We were the first to demonstrate that when a brain cell is under oxidative stress conditions, the cell’s pump, the one that moves cystine into the cell, went from inside the cell to its surface and stayed put on its membrane.”

Their research also documented for the first time that when that pump is working on the cell membrane, glutathione levels within the cell increase rapidly. “And as glutathione levels went up and the oxidative stress in the cells went back down, that pump returned back inside of the cell. That was a really interesting discovery.”

In late 2018 Chase and her student research group submitted an article about this research to a scientific journal.

This year, she’s exploring another angle: why the glutathione-cystine-pump triad may go haywire. It’s made up of 501 amino acids, and she and her students are identifying which of them respond to changes in oxidation states and force the pump to move to the membrane. This will increase their understanding of the molecular players that regulate the pump’s response to oxidative stress. Eventually, Chase hopes to team up with other scientists who have access to tissue samples from Parkinson’s patients, perhaps at the Van Andel Institute in Grand Rapids. As she compares the cystine pumps in cells taken from people who have Parkinson’s disease and people who don’t, and considers the molecular players involved in its regulation, Chase will continue to ask that ubiquitous research question: What’s different?

“There’s a variety of things we can look for,” Chase says, “but my guess is that for most people, Parkinson’s has an environmental cause. My gut tells me it wouldn’t be that simple as a little mutation in the cystine pump.” Chase was the founding director of Hope’s neuroscience program in 2005 and has directed it ever since. The wonder of cells and how they work makes her marvel at the intricacies of the human brain. As an undergraduate at the University of Michigan-Flint, Chase considered a career as a physician. She chose instead to make an impact on the medical world, and people with Parkinson’s disease in particular, from the realm of a research lab. (She also does research on bipolar disorder, which has involved collaborations with Hope psychologist Dr. Andrew Gall, Hope chemist Dr. Ken Brown and retired Hope biology professor Dr. Christopher Barney.)

“It’s truly my interest to do research that will eventually be helpful to those who do the translational research,” she says. “Our research is the basic science needed in order for somebody, someday to fix the problem with a new drug. If we can find where the problem is, and that can help somebody else who has access to patients, then that would be fantastic.”