Researchers have identified a protein that worsens symptoms of Parkinson's disease.

Scientists have long known that a drop in dopamine—an important chemical in the brain—is associated with Parkinson's. And for decades patients have taken a drug called Levodopa to boost the brain's dopamine levels. Unfortunately, however, Levodopa's efficacy begins to fade as the disease progresses. So scientists have begun looking for other targets for which they can develop new therapeutic strategies.
"About 60,000 Americans are diagnosed with Parkinson's annually, and dopamine-based therapies often do not provide a long-term solution," said Dr. Kreitzer, who is also an assistant professor of physiology and neurology at UCSF, with which Gladstone is affiliated. "Our discovery that RGS4 may play a role in the development of Parkinson's symptoms, helps us lay the groundwork for a new therapeutic strategy—independent of dopamine."
Drs. Kreitzer and Lerner found that RGS4 is required for dopamine to regulate brain circuits during learning. But when dopamine levels drop dramatically, as in Parkinson's, RGS4 becomes overactive and disrupts these circuits—thereby leading to Parkinson's symptoms. Therefore, they tested whether removing RGS4 could prevent these symptoms.
Drs. Kreitzer and Lerner treated mice lacking RGS4 with a chemical that lowers dopamine levels, mimicking the effects of Parkinson's. They then monitored the mice's motor skills—including their ability to move freely in an open arena and traverse a balance beam—and compared them to Parkinson's mice in which RGS4 remained intact.
As expected, Parkinson's mice with RGS4 intact exhibited major problems with movement. They lacked coordination and often remained frozen in place for long periods of time. When attempting to cross the balance beam, many had repeated slips and falls, while others could not even attempt the task.
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"By discovering how the removal of RGS4 affects brain circuitry at the molecular level, we gained a deeper understanding of the protein's role—both normally and in Parkinson's disease," said Dr. Lerner. "We've also shed light on a previously unknown mechanism by which the dopamine depletion causes the symptoms of Parkinson's disease. We are optimistic that our work could pave the way for a much-needed alternative to Levodopa—such as a drug that has the ability to inactivate RGS4 in Parkinson's patients."
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