By shifting a normal protective mechanism into overdrive, a University of Wisconsin-Madison scientist has completely shielded mice from a toxic chemical that would otherwise cause Parkinson's disease.
Parkinson's disease is a disabling and sometimes fatal disease that afflicts 1.5 million Americans, with about 60,000 new cases annually. Its major symptoms, including tremors and sluggish movement, have been traced to death of small numbers of nerve cells in the substantia nigra, a brain region that helps regulate movement.
Adding extra copies of a gene that makes a normal, protective protein neutralized a toxic chemical that would normally devastate the substantia nigra. "This complete abolition of toxicity was far greater than we expected," says Jeffrey Johnson, a UW-Madison professor of pharmacy. "It was striking. We thought we would see a 20 or 30 or 40 percent reduction in cell death."
The protective mechanism is initiated by a protein called Nrf-2, which is present in people and in mice, says Johnson. Nrf-2 (transcription factor NF-E2-related factor) is made by astrocytes, brain cells that play a supportive role to the neurons, which are the cells that actually carry nerve signals.
In recent years, researchers looking at a range of neurodegenerative diseases, including Alzheimer's and Lou Gehrig's diseases as well as Parkinson's, have focused on the astrocytes in their quest to help the brain protect itself from stressful conditions that are deadly to neurons. "Astrocytes way outnumber neurons and are found throughout the central nervous system," says Johnson. "Neurons have always gotten the Academy Awards, but astrocyte dysfunction is becoming a central theme in neurodegenerative disease. If we can figure out how to fix a sick astrocyte, or even prevent it from getting sick, that could offer profound protection against almost all neurodegenerative diseases."
Because neurons are impossible to replace, the present research focus in neurodegenerative disease is on preventing their death in the first place. Parkinson's disease can be treated for a time by replacing dopamine, the brain chemical made by the substantia nigra, but the treatment loses its efficacy over time.
In a study funded by the National Institute of Environmental Health Sciences and published in today's Proceedings of the National Academy of Sciences , Johnson and UW-Madison colleagues Pei-Chun Chen, Marcelo Vargas and Delinda Johnson studied mice with extra Nrf-2 genes. The astrocytes in these mice produced about twice the normal level of Nrf-2 protein.