What does one do when a good protein goes bad?
That's the question raised by researchers at the University of California, San Francisco's Gladstone Institute. They've identified a protein that aggravates the symptoms of Parkinson's disease when dopamine levels drop. Dopamine is the chemical neurotransmitter responsible for smooth muscle movement. Treatment for PD symptoms tend to revolve around replacing the brain's depleted dopamine supply.
In a paper published Jan. 25 in the online journal Neuron
, researchers describe how a protein known as RGS4 normally regulates the activity of neurons in the striatum. That's the part of the brain that controls movement. The paper, written by Gladstone Investigator, Dr. Anatol Kreitzer and Dr. Talia Lerner, who worked at Gladstone while completing her graduate studies at the UCSF, shows how RGS4 is needed for dopamine to regulate brain circuits during learning. But when dopamine levels drop dramatically, as in Parkinson’s, RGS4 goes from being a "good guy" to a "villain", interrupting and disrupting the circuitry, causing Parkinson’s symptoms.
Would removing RGS4 make a difference?
The researchers used mice that had no RGS4 alongside mice that had RGS4 and then gave them a chemical that mimics Parkinson's disease in animals. The mice that had the protein showed signs of Parkinson's disease, including loss of balance and coordination along with freezing of gait.
The mice with no RGS4? No problem. They could make it across a balance beam without falling. They showed no signs of Parkinson's disease.
This discovery is important since the current gold standard for Parkinson's disease therapy is dopamine replacement, with a drug combining levodopa and carbidopa which the brain converts into dopamine. But the drug loses effectiveness after a period of years.
"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," Dr. Lerner said.
This research was funded by a variety of sources, including the National Institutes of Health, as well as the Pew Biomedical Scholars Program, the W.M. Keck Foundation and the McKnight Foundation. The Gladstone Institute is an independent and nonprofit biomedical-research organization dedicated to accelerating the pace of scientific discovery and innovation to prevent illness and cure patients suffering from cardiovascular disease, neurological disease, or viral infections.
(FULL DISCLOSURE -- the author of this article was a writer/editor for the National Institutes of Health for six years before retiring due to advanced Parkinson's disease.)