Gene Expression Changes in Striatal Cholinergic Interneurons Associated with Levodopa-induced Dyskinesia

Study Rationale:                   
In pre-clinical models, we identified an important role of cholinergic interneurons — which release the neurotransmitter acetylcholine — from part of the brain called the striatum in levodopa-induced dyskinesia. This small population of striatal neurons has not been well studied in Parkinson’s disease (PD) models and may present a new therapeutic target. Examining gene expression profiles in published data showed selective expression of molecules that can be targeted for therapeutic uses in nonparkinsonian models, providing a proof of principle to apply such approach for development of novel therapeutic targets for PD. We will carry out a similar approach for PD and dyskinesia models.

Hypothesis:
We hypothesize that selective gene expression profiles of striatal cholinergic interneurons in dyskinetic models will reveal molecular changes that can be targeted for therapy.

Study Design:
We will utilize a model to identify distinct gene expression profiles in this type of neuron. We will compare them in dyskinetic and non-dyskinetic, but parkinsonian, models, to identify different patterns for each state.

Impact on Diagnosis/Treatment of Parkinson’s Disease:             
The data obtained will provide an insight on specific molecular changes in striatal cholinergic neurons that may reveal potential targets for therapeutic manipulation.

Next Steps for Development:
Once we identify specific molecular changes in the striatal cholinergic neurons associated with dyskinesia, they will be targeted for therapy of dyskinesia.