Scientists at The Burnham Institute recently reported in Science magazine that an short lived gas, called nitric oxide, found in the body and as an air pollutant, can activate enzymes on the outside of nerve cells to trigger their demise during stroke and neurodegenerative diseases, such as Alzheimer's disease, multiple sclerosis, and AIDS dementia.
The enzymes belong to a family known as matrix metalloproteinases or MMPs. When activated in excess, these enzymes chew up the outside of nerve cells, resulting in their death.
"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 could activate these enzymes was not previously recognized," commented Lipton.
Using an intricate chemical approach called mass spectrometry, which allows precise characterization of proteins and enzymes, the scientists found that the MMP enzymes are not only activated by nitric oxide, but also that the MMPs are further affected by oxygen-related molecules to produce permanent activity of the enzymes, leading them to destroy 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.
"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.