Biomedical Frontiers: SPRING/SUMMER 1997, Vol.4, No.3
Special Section: Alzheimer's Research
The Role of Caspase Enzymes

The death of neurons is an element of all neurodegenerative disorders. At CPMC, researchers are slowly revealing the molecular mechanisms behind the caspase enzymes involved in neuronal cell death. The results of their work may lead to treatments for neurodegenerative disorders such as Alzheimer's disease.

"There are two ways to stop a disease: One--the best way--is to know the cause and remove it. The other is to stop the disease even though the cause remains," says Dr. Michael Shelanski, Delafield Professor and Chairman of pathology and co-director of the Taub Center for Alzheimer's Disease Research. "In Alzheimer's disease there may be many causes, and except for a small number of genetic cases, we don't yet know what they are. But we do know that proper contact between neuronal cells is lost and the cells become non-functional and die."

Scientists recognize at least two main pathways to neuronal cell death: oxidative stress and trophic factor deprivation. In a study published in a May issue of Proceedings of the National Academy of Sciences, CPMC researchers found that completely blocking the action of caspase enzymes (formerly called the ICE family of proteases) blocked both pathways. The researchers used a unique inhibitor to accomplish this--a pseudo-enzyme designed by Dr. Carol M. Troy, lead author of the study and assistant professor of pathology. "All other known caspase inhibitors are pseudo-substrates. But with a pseudo-substrate, you have to know what the substrate is," she says. "We didn't know what the death substrate was, so we designed a pseudo-enzyme instead." This pseudo-enzyme will block all caspases containing the conserved active "site." A patent application for the pseudo-enzyme has been filed.

In another study, researchers looked specifically at the results of blocking Nedd-2 (a caspase) in the cell. Dr. Troy and colleagues used an antisense oligonucleotide (for which a patent application has been filed) to decrease Nedd-2. The results, published in a March issue of the Journal of Neuroscience, indicate that decreasing Nedd-2 blocks trophic factor cell death, but not oxidative death. Previous studies by the same group have shown that oxidative cell death involves interleukin-1 beta converting enzyme (ICE) and nitric oxide.

The researchers are now looking at exactly what happens to Nedd-2 in the cell. "When a neuronal cell is dying, are there different things happening in the processes vs. the body?" asks Dr. Troy. "Are there caspases mediating it? What's the fine-tuning? Where are the caspases localized?"

The team of researchers investigating caspases is made up of Drs. Troy, Shelanski (senior author), Leonidas Stefanis, and Lloyd Greene.