Sentry enzyme blocks paths to Parkinson's disease

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The degeneration of brain cells that occurs in Parkinson’s disease can 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 results of studies in mouse models by St. Jude investigators.

In Parkinson’s disease, nerve cells in the 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”) that 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 that appears in the February 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 (“suicide”), triggered by certain stressful conditions in the cell. If GST pi levels are reduced or this enzyme is overwhelmed by toxins, the dopaminergic neurons are at an increased risk of death.

The finding that GST pi plays a key role in preventing Parkinson’s 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, PhD, Developmental Neurobiology. “And 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.

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.

Michelle Smeyne, Developmental Neurobiology, and former employees Justin Boyd and Kennie Raviie Shepherd did most of the work on this project; other St. Jude authors include Yun Jiao, MD, and former employees Brooks Barnes Pond and Matthew Hatler.