The degeneration of brain cells that occurs in Parkinson’s disease may be caused by either externally provoked cell death or internally initiated suicide when the molecule that normally prevents these fatal alternatives is missing, according to studies in mouse models by investigators at St. Jude Children’s Research Hospital.
Parkinson’s disease is a disease in which nerve cells in part of the brain called the substantia nigra die, resulting in the loss of dopamine, a nerve-signaling molecule that helps control muscle movement. The absence of dopamine from these cells, called dopaminergic neurons, causes a loss of muscle control, trembling and lack of coordination.
The molecule that prevents damage to the substantia nigra is an enzyme called GST pi ("pie"). This molecule stands like a sentry at the crossroads of several biochemical pathways, any one of which can lead to Parkinson’s disease, the researchers reported in an article in the Feb. 1 early online edition of Proceedings of the National Academy of Sciences.
The job of the antioxidant GST pi is to protect the cell from death caused by either environmental toxins (externally evoked cell death), such as herbicides and pesticides, or a self-destruction process called apoptosis (cell suicide), triggered by certain stressful conditions in the cell. If GST pi levels are reduced or this enzyme is overwhelmed by toxins, these nerves are at increased risk of death. Previous research has shown that the ability of GST pi to protect cells against toxic molecules is directly linked to the ability of cancer cells with excessive amounts of this enzyme to reduce the effectiveness of chemotherapy.
The finding that GST pi plays a key role in preventing Parkinson’s disease suggests that measuring levels of this enzyme might be an effective way to determine individuals at risk for developing this disease, according to Richard Smeyne, Ph.D., an associate member of the Department of Developmental Neurobiology at St. Jude. "In the future, treatments that increase GST pi levels in the substantia nigra might help to prevent or delay the onset of Parkinson’s disease or reduce its severity," said Smeyne, the report’s senior author.
GST pi is one of a family of similar enzymes that eliminate free radicals generated by pesticides and other chemicals. Two members of this family are present in the brain, but only one of them, GST pi, is found in the dopaminergic neurons of the substantia nigra. Free radicals are highly unstable molecules that readily interact with other molecules, causing cell damage.
The study sheds light on the cause of most cases of Parkinson’s disease, which currently are unexplained. "The majority of these cases of Parkinson’s disease appear to arise because individuals who have a genetic susceptibility to the disease are exposed to environmental toxins such as pesticides and herbicides, which trigger the formation of free radicals that kill dopaminergic neurons in the substantia nigra," Smeyne said. "We also know that GST pi blocks the process of cell suicide triggered by stresses that the cell can’t overcome, such as an increase in the presence of free radicals or a loss of the cell’s ability to produce energy."
