Tumor-control gene may play role in death of brain cells

p53 is a killer gene. It initiates programmed cellular suicide so that genetically damaged cells do not accumulate and form tumors. Doctors know this primarily because mutations of p53 are seen in over half of all cancers. Hence its nickname, the “tumor suppressor” gene.

But p53 has a sinister side. Sometimes, scientists say, p53 pushes cells over the edge when it isn’t necessary. In fact, Dr. Richard Morrison suggests that p53 may play a role in neurodegenerative diseases such as Alzheimer’s and in the neuronal cell death that occurs after brain injury.

A professor of neurological surgery, Morrison conducts studies in which he intentionally inhibits p53. In some studies, he actually eliminates it completely. “When we first started this research, people said, ‘Don’t do that, it will cause cancer,’” he said. “That is not what we are doing.”

Neurons continue to die in subjects up to three weeks after a brain injury, such as a stroke, Morrison explains. By mimicking the chemical environment that exists after a brain injury, Morrison discovered that when p53 is absent, these neurons do not die. Somehow, via a very complex network of intracellular chemical interactions, p53 initiates cell suicide.

Richard Morrison Photo by Gavin Sisk

Morrison will discuss his research in detail in a Science in Medicine Lecture titled, “Brain Drain: Preventing Neuronal Cell Loss Through an Understanding of Cell Death Signaling Pathways,” on Thursday, April 6, from noon to 1 p.m. in room T-625 of the Health Sciences Center.

When a person experiences a brain injury, damaged or dying neurons release an excitatory amino acid called glutamate. Excessive exposure to glutamate overexcites neurons. The DNA in the nucleus of an overexcited neuron can become damaged. When this damage is too severe for the cell to repair itself, it dies. This is the process p53 is thought to regulate.

In a study that has been accepted for publication in the Journal of Cell Biology, Morrison describes part of the mechanism. When the neuron is exposed to elevated levels of glutamate, a protein called Bax in the cytoplasm of the cell also increases. Using fluorescent microscopy to “mark” Bax, Morrison observed that under such conditions, Bax actually moves within the cytoplasm of the cell and attaches to the mitochondria. There, the protein appears to block an important step in the cell’s ability to maintain energy levels and survive.

The mechanism only occurs in the presence of p53, Morrison explains. This suggests that Bax is one of the players “downstream” from p53 involved in abnormal cell death. In other words, p53 is signaling Bax to kill the cell.

The same mechanism may be triggered in neurons over years in Alzheimer’s patients, Morrison suggests. “We may be working with divergent initiators of damage, but there may be common mediators in the middle and at the end of the cell death process. That’s part of what we’re trying to figure out,” he said.

Ultimately, Morrison and colleagues want to find a way to intervene in this “brain drain” and restore cognitive or motor function in Alzheimer’s patients or people who have experienced brain injury. If researchers can inhibit one of the steps in the process for several weeks after brain injury, perhaps they can save the patient’s neurons.

Some studies suggest that neuroregeneration - actively initiating the growth of neurons in the brain - is possible. But by and large, Morrison believes, researchers are better off trying to prevent these cells from dying in the first place.

Many more steps in cell death will need to be understood. Which step along the way do they need to stop? The key is to find a way to prevent p53 from initiating death in neurons that still allows the gene to continue to recognize and initiate the death of cancerous cells. Another question is, if researchers intervene in cell death and manage to keep damaged neurons alive, how well will they work?

“The cells that remain will need to be functionally viable as well as physically present,” Morrison said.

Morrison received a Ph.D. in anatomy in 1982 from the University of California, Los Angeles. He joined the UW in 1994 as an associate professor of neurological surgery. ¶

Will Morton