Scientists at the University of California at San Francisco identified a protein that could be a drug target for treating Parkinson's disease, a neurodegenerative disorder that affects more than 10 million people worldwide.

Parkinson's disease affects the basal ganglia, a part of the brain that controls complex movements. In Parkinson's patients, for reasons that are still largely unknown, dopamine-containing neurons die off, leaving patients with tremors and unable to initiate complex movements such as walking.

But how?

Just how dopamine affects movement, and more generally, what its downstream effects are, is "something that people have been trying to figure out for 50 years," Anatol Kreitzer told BioWorld Today. "There have been hundreds, if not thousands, of papers on the topic."

Kreitzer is an investigator at the Gladstone Institutes, a research institute that is affiliated with the University of California at San Francisco. He is also the senior author of the paper reporting the findings, which appeared in the Jan. 26, 2012, issue of Neuron.

The dying neurons themselves are located in the substantia nigra. But they project onto another part of the basal ganglia, the striatum. There is both a direct and an indirect pathway from the substantia nigra to the striatum. Kreitzer said that "an overactive indirect, and maybe an underactive direct, pathway has long been proposed to be involved in Parkinson's disease."

A few years ago, Kreitzer and his colleagues demonstrated in animals that the indirect pathway does inhibit movement. Activating that pathway inhibits movement, mimicking the symptoms of Parkinson's disease.

In their current study, Kreitzer and first author Talia Lerner worked out the molecular mechanisms that underlie that inhibition. In their work, they focused on the molecular cascade downstream from one type of dopamine receptor, the D2 receptor, which is expressed on neurons of the indirect pathway. In doing so, they deciphered a pathway that went from dopamine receptor activation to plasticity to motor behavior.

The neurons that respond to dopamine also have another receptor, the A2A receptor, whose effect on intracellular pathways is the opposite of dopamine. Together, the two receptors control intracellular pathways that control plasticity of the neurons, effectively controlling how sensitive they will be to incoming stimuli. They work, in part, by controlling the levels of the protein RGS4.

Kreitzer and Lerner looked at RGS4 because the protein has characteristics that would be expected of a protein that is affected by the signaling pathway controlled by dopamine and A2A. "And sure enough, if we knocked out RGS4, dopamine and A2A no longer controlled plasticity."

Normally, activation of the two pathways balances each other. But when dopamine disappears, the signaling system gets out of balance. The net result is that the inputs lose one form of plasticity, and the indirect pathway becomes hyperactive and inhibits movement.

Kreitzer and Lerner next tested whether their work might allow them to influence motor behavior through RGS4 rather than dopamine. "We asked, 'Now that we've got this pathway figured out, can we just skip the dopamine?'" And indeed, it turned out they could.

The brain cells of knockout mice missing the RGS4 protein retained that plasticity when their brain levels of dopamine were low. And when the animals were treated with a toxin that kills dopaminergic neurons, essentially giving them chemically induced Parkinson's disease, RGS4 knockouts were less impaired in their movements than control animals.

Currently, no clinically suitable inhibitors of the protein RGS4 exist that might be used to test whether the same approach could work in humans. But Kreitzer told BioWorld Today that his team "would love to develop RGS4 inhibitors."

Such an approach might avoid the shortcomings of Levodopa, the dopamine precursor that is the first line of treatment for Parkinson's disease. Levodopa works, but it tends to lose its effectiveness over time – and in bad cases, can lead to psychiatric side effects that include psychosis.

"If you could find a good compound," Kreitzer said, "I think it could potentially be a real game-changer for Parkinson's disease."