Parkinson's disease is a debilitating movement disorder affecting up to 2 in 1000 people worldwide. Parkinson's disease is caused by an irreversible loss of dopamine signal to the striatum, a region of the brain that fine-tunes our movements. Current treatments against this disorder, most of which function by acting as chemical substitutes for dopamine, are effective, yet limited by their side effects. L-DOPA was one of the first such treatments, and is still the most effective against the effects of Parkinson's disease. Unfortunately L- DOPA inevitably leads to uncontrollable involuntary movements of the limbs-a debilitating condition termed L- DOPA induced dyskinesia, or LID. Years of study have yet to produce a coherent explanation for this side- effect-just now are we beginning to understand that it is caused, in part, by an inability of our brain to self- regulate its response to the dopamine signal restored by L-DOPA treatment. It seems that the initial loss of dopamine increases sensitivity of the striatum to any subsequent stimulation, and that this 'supersensitivity'is worsened by repeated L-DOPA treatments. The neural circuits of the brain depend upon a well-documented cascade of protein interactions to limit excessive response to neurotransmitters like dopamine. This system of self-regulation relies upon two key proteins, the GPCR kinases, or GRKs, and the arrestins, to adequately control dopamine signal. Recent studies have discovered that both Parkinson's disease and L-DOPA treatment cause a change in the level of these GRKs and arrestins within the striatum, thus limiting the ability of the striatum to regulate excessive dopamine signaling. This study is designed to illustrate the effectiveness of gene therapies that increase the function of GRKs and arrestins in the striatum, to treat LID. The study will also serve to further current understanding as to how these two proteins function to restore normal dopamine signal control in the parkinsonian striatum. The first experiment proposed consists of testing, in animals designed to model Parkinson's disease, the ability of gene therapies engineered to express either the GRK3 isoform alone, or in combination with arrestin3, to limit the severity of LID. The second experiment in the study will use a similar strategy to model Parkinson's, but will use a virus that actually hinders the function of GRK3 in the striatum-if found that decreased GRK3 function makes LID more severe, it can be concluded that GRK3 dysfunction does play a role in the actual development of LID. The final experiment proposed is an examination, at the molecular level, of all the brains from animals used across the first two experiments. Focusing upon two specific markers of dopaminergic signaling, known to be affected by both Parkinson's and LID, namely ERK and Akt activation, conclusions as to any ameliorative effects of GRK and arrestin gene therapy can be made. The study expects to find that the gene therapies functioned to actually restore normal dopamine signal control, rather than just alleviating the behavioral effects through some other, yet unexplained means.

Public Health Relevance

Though L-DOPA remains the most effective treatment against Parkinson's Disease, its prolonged use is impeded by a single debilitating side-effect-the uncontrollable movements of L-DOPA induced dyskinesia (LID). This study aims to explain the molecular mechanisms behind LID as well as test cutting-edge gene therapies against LID. By the end of this study, two novel drugs targets and the proof-of-principle for gene- therapies against LID will have been tested in a live rat model of Parkinson's disease and LID.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01-L (20))
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Sieber, Beth-Anne
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Vanderbilt University Medical Center
Schools of Medicine
United States
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