June 25, 2010

New target for improving Parkinson’s treatment

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Eugenia Gurevich, Ph.D., Mohamed (Rafi) Ahmed, Ph.D., and colleagues are studying a protein associated with a side effect of the Parkinson’s disease medication L-dopa. (photo by Mary Donaldson)

New target for improving Parkinson’s treatment

Parkinson's disease, a neurodegenerative disorder that impairs movement, can often be successfully treated with the medication L-dopa. Over time though, L-dopa's effectiveness wanes and troubling side effects crop up, including dyskinesia — involuntary purposeless movements.

Researchers from Vanderbilt University Medical Center and the University of Bordeaux in France recently reported that boosting the brain expression of a regulatory protein called GRK6 relieved L-dopa-induced dyskinesia in monkey and rat models of Parkinson's disease. The findings, published in Science Translational Medicine, suggest a new approach for treating dyskinesia in Parkinson's disease.

“Dyskinesia is very difficult to control,” said Eugenia Gurevich, Ph.D., associate professor of Pharmacology at VUMC. “Whatever you do to suppress the dyskinesia usually ends up suppressing the beneficial effects of the L-dopa; it's very hard to separate the two.”

The challenge arises because both the beneficial and the adverse effects of L-dopa appear to depend on signaling by dopamine receptors.

In Parkinson's disease, brain neurons that send signals using the neurotransmitter dopamine degenerate. These dopamine-signaling neurons control voluntary movement, so when they are lost, patients experience muscle rigidity, tremor, and slowing or loss of movement.

In an effort to compensate for the loss of dopamine, neurons that are regulated by dopamine produce super-sensitive dopamine receptors — these receptors respond vigorously to dopamine, including the dopamine generated after a patient takes L-dopa. But super-sensitive dopamine receptors and the “waves” of dopamine that follow periodic doses of L-dopa “ruins the normal control of dopaminergic signaling,” Gurevich said.

This normal control involves regulatory proteins called GRKs (G protein-coupled receptor kinases). GRKs “turn off” activated receptors in a process called desensitization. Gurevich and colleagues postulated that this process becomes deficient during the course of Parkinson's disease and L-dopa treatment, contributing to uncontrolled dopamine signaling and dyskinesia.

“We thought if we could increase the capacity of this regulatory system, maybe it could rein in the signaling and alleviate the dyskinesia,” Gurevich said.

The investigators used a gene therapy approach — they developed a lentivirus to deliver the GRK6 gene to affected brain areas in animal models of Parkinson's disease, to increase the levels of the GRK6 protein.

The results in rats were encouraging: GRK6 alleviated dyskinesia-like symptoms. So the VUMC researchers teamed with Erwan Bezard, Ph.D. in France to pursue studies in parkinsonian monkeys, the “gold standard” for Parkinson's research because the course of the disease — its symptoms and response to treatments — closely resembles Parkinson's disease in humans.

They found that in GRK6-expressing parkinsonian monkeys, the L-dopa-induced dyskinesia was substantially reduced, and — much to their surprise — that the therapeutic effect of L-dopa lasted longer. With a half-strength dose of L-dopa, the GRK6-expressing monkeys had no dyskinesia and had the same magnitude of therapeutic benefit as control monkeys getting a full dose of L-dopa.

“We actually achieved what I thought was impossible — we reduced dyskinesia and we improved the therapeutic effect of L-dopa. We couldn't believe it at first,” Gurevich said.

“GRKs — and the receptor desensitization machinery — are viable targets for developing treatments that could combat dyskinesia and motor fluctuations (worsening of response to L-dopa) in Parkinson's patients. That would really improve treatment.”

The investigators are continuing to explore how GRKs enhance L-dopa action, which GRKs work best (there are three more in addition to GRK6), and whether drug-like chemicals could be used to increase GRK expression.

They are also pursuing other conditions of excessive receptor signaling, such as drug abuse, where targeting the regulatory machinery may have therapeutic potential.

Mohamed (Rafi) Ahmed, Ph.D., research fellow in Pharmacology, is the lead author of the study. The National Institutes of Health, Michael J. Fox Foundation for Parkinson's Research, and Agence Nationale de la Recherche, France, provided funding for the research.