Protective protein may hold key to halting progression of neurological diseases

Jan. 11, 2005

by Aaron Conklin

Patients who suffer from neurological diseases such as Huntington's disease, Parkinson's, Lou Gehrig's disease (ALS) and Alzheimer's disease have dramatically different symptoms. An Alzheimer's patient, for instance, will lose memory and cognitive function, while an ALS sufferer will gradually lose motor control.

To doctors and researchers, however, how brain cells die in these diseases actually is quite similar. The diseases operate in similar ways and in particular are associated with common events within a cell that lead to cell death.

By using a protein that supercharges the cell's defense mechanisms, a team of researchers led by Jeff Johnson, associate professor in the School of Pharmacy, may have found a way to block this common event from occurring and halt the progression of these diseases. The work of Marcus Calkins, a molecular and environmental toxicology graduate student in Johnson's lab, appeared in the Jan. 4 edition of the Proceedings of the National Academy of Sciences.

Within the cell, the mitochondria function as a sort of power plant, directing and regulating energy to fight off natural toxicities and keep cells functioning normally. As a person ages, the "power plant" begins to slow down, and the cell's natural defense mechanisms begin to fail. Eventually, cell toxicities overwhelm the defense mechanisms, causing neurons in the brain to begin dying. In certain individuals, this is the beginning of the long, slow path into neurodegenerative diseases such as Huntington's and Parkinson's.

That's where a substance called Nrf2 comes in.

"Nrf2 is a protein that, when you put it into cells, it brings up all the defense mechanisms simultaneously. Not only do you increase the cell's endogenous antioxidants, but you're also increasing the enzymes that remove toxicities from the cell," says Johnson. "The protein also has a global effect — it doesn't just protect that which is inside, but also the normal cells in and around its environment."

To test their hypothesis, Johnson and his research team transplanted cells with a high expression of Nrf2 into the brains of mice. After about five weeks, the team began exposing mice to toxins that kill neurons, the same neurons that are lost in Huntington's disease.

The result? "The Nrf2 seems to completely protect the mice from toxicity," says Johnson.

Based on this initial finding, Johnson speculates that it may be possible, within the next three to five years, to transplant cells containing the Nrf2 protein into the human brain. The protein could work to halt the progression of early-stage Alzheimer's, ALS and Parkinson's. In patients at high risk of developing Huntington's disease, a condition with a known genetic component, Nrf2 could prevent or delay the disease from occurring.

"What's exciting about this discovery is that we're really starting to learn something about how the brain is able to protect itself from injury," says Calkins, who admits surprise at how effectively the Nrf2 protected the mouse brain cells. "The hope is that we can exploit this natural defense mechanism to benefit people who suffer from neurodegenerative disease."

Johnson's lab is also searching for a molecule that could activate the normal Nrf2 in human brain cells and that could be delivered in the form of a pill.

"From the drug development standpoint, we already have a number of molecules in the pipeline," says Johnson. "Realistically, I would hope we could have something ready for testing in humans in the next two to four years."

Interestingly, Johnson arrived at his core hypothesis based on research into cancer treatment. He noticed that patients who received chemotherapy would often have tumors that diminished, then returned, growing stronger each time. Eventually, the chemotherapy drugs became ineffective.

"What the tumor cells did was to modify themselves to become resistant by dramatically increasing their protective antioxidants," Johnson explains. "If you look at it intuitively, you can say that what we've done is to select for a very strong cell. The question is, can we generate a strong cell without it being cancerous? And it looks like we can."

The next step is to test the Nrf2 hypothesis on primates and humans. Johnson's research is funded by the National Institutes of Environmental Health Sciences.