"The new work uncovers the mechanism of activation of an enzymatic pathway that leads to nerve cell death," said Stuart A. Lipton, M.D., Ph.D., a neurologist who is Professor and Director of the Center for Neuroscience and Aging at The Burnham Institute, and head of the team reporting the new findings. "The MMP enzymes act outside of the nerve cell rather than inside," Lipton continued. Previously, the best characterized enzyme pathways that killed nerve cells were found inside nerve cells rather than outside. "The new results also link two previously unrelated scientific fields studying MMP enzymes and nitric oxide gas, both of which were thought to be important in the life and death of nerve cells, but the fact that nitric oxide [abbreviated NO] could activate these enzymes was not previously recognized," commented Lipton.
Using an intricate chemical approach called mass spectrometry, which allows precise characterization of proteins including enzymes, the scientists found that the MMP enzymes are not only activated by NO, but also that the MMPs are further affected by oxygen-related molecules to produce permanent and pathological activity of the enzymes, leading them to chew up the normal environment surrounding the nerve cell. This heightened activity occurs predominantly during periods of stress or disease, and results in the death of the nerve cells by a process known as apoptosis.
"Now that we know about this new pathway to nerve cell death that occurs outside of the cells, we can design drugs to interrupt it, and that is where the work will go in the future," said Dr. Lipton. He and his colleagues are starting to test such drugs in stroke models in rodents. "The work gives us a new way to think about preventing excessive activity of MMP enzymes, and as such it could lead to new therapies for stroke and several neurodegenerative diseases," said Lipton.
This discovery was borne of an inter-disciplinary collaboration at The Burnham Institute making use of expertise on the signaling of matrix metalloproteinases gained in the context of cancer research (Dr. Alex Strongin), the functional analysis of proteins, or proteomics (Dr. Jeffrey Smith), and structural analysis of proteins (Dr. Robert Liddington). Other contributors included research assistant professor Marcus Kaul and postdoctoral fellows Zezong Gu, Boxu Yan, Steven J. Kridel, and Jiankun Cui.
This research was funded in part by grants from the National Institutes of Health.
The Burnham Institute (www.burnham.org) is an independent, nonprofit, public benefit organization dedicated to basic biomedical research in cancer, aging, and neurosciences. The Institute's Cancer Center is recognized by the National Cancer Institute as a non-comprehensive Cancer Center for basic research. Dr. Stuart Lipton directs the Institute's Del E. Webb Center for research on neurodegenerative diseases and aging. The Burnham Institute ranks consistently among the world's most influential research organizations for the impact of its research in annual surveys conducted by The Institute for Scientific Information.
Journal
Science