Objective/Rationale:
Levodopa remains the most efficient agent used for the Symptoms & Side Effects treatment of Parkinson’s disease. Unfortunately, levodopa administration for several years also induces severe secondary effects known as dyskinesia. Such secondary effects seriously limit the therapeutic efficacy of levodopa. In order to improve the treatment of Parkinson’s disease, it is therefore critical to understand the mechanisms involved in levodopa-induced dyskinesia. The objective of the project is to demonstrate the key role of the Gad1 gene and its protein product in the development of levodopa-induced dyskinesia.
Project Description:
The role of the Gad1 gene in levodopa-induced dyskinesia will be determined in genetically modified pre-clinical models. Pre-clinical models with a Gad1 deletion in neurons of the striatum and in control models will receive chronic administrations of levodopa. The effect of the Gad1 gene deletion on the development and severity of levodopa-induced dyskinesia will be measured. It is expected that the Gad1 gene deletion will decrease the severity of levodopa-induced dyskinesia. In other experiments, the effect of Gad1 gene deletion on synaptic activity at synapses using GABA as their neurotransmitter will be measured. This will determine the critical contribution of GABAergic neurotransmission to levodopa-induced dyskinesia.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Levodopa-induced dyskinesia represent a major secondary effect induced by current pharmacological treatments of Parkinson’s disease. There are currently no known agents that can completely prevent or reverse levodopa-induced dyskinesia while maintaining the antiparkinsonian efficacy of levodopa. The identification of the role of Gad1 and GABAergic neurotransmission in levodopa-induced dyskinesia will impact the treatment of Parkinson’s disease by identifying new pharmacological targets for this disorder.
Anticipated Outcome:
This work will demonstrate the key role of the protein Gad1 and of GABAergic neurotransmission in the detrimental secondary effects induced by the therapeutic agent levodopa. This will lead to a better understanding of the basic cellular and molecular mechanisms involved in levodopa-induced dyskinesia. The work will also help us understand the role of Gad1 in the control of movement.
Progress Report
The project’s major objective is to elucidate a key molecular mechanism involved in levodopa-induced dyskinesia. Specifically, we are determining if the protein encoded by the gene Gad1 plays a key role in the development of levodopa-induced dyskinesia. In order to reach this goal, we have been breeding and maintaining several lines of genetically-modified pre-clinical models. These models were successfully used to induce a loss of Gad1 expression in neurons of the striatum in brain. We are now carrying out experiments to show that the loss of Gad1 prevents the development of dyskinesia induced by levodopa in the pre-clinical model of levodopa-induced dyskinesia.
Final Outcome
The main hypothesis tested in this project is that abnormal expression of the protein Gad1 is involved in levodopa-induced dyskinesia. In order to test this hypothesis, we developed a genetically modified line of pre-clinical models with a conditional Gad1 deletion in direct and indirect pathway neurons of the striatum. Our observations indicate that this manipulation does not prevent levodopa-induced dyskinesias. This result, however, does not completely rule out a role of Gad1 in l-DOPA-induced dyskinesias. Current studies are carried out to determine if Gad1 removal in the direct pathway alone will improve levodopa-induced dyskinesias.