A Small Molecule Approach to Correct Striatal Cholinergic Interneuron Dysfunction

Objective/Rationale:
There is growing evidence that cholinergic interneurons (ChIs) in the striatum undergo maladaptive biochemical changes leading to their hyperactivation under conditions of levodopa induced dyskinesia (LID).  We propose here an approach to precisely target hyperactive ChIs through a non-cholinergic receptor mechanism using small molecules and to validate its potential in treating Parkinson’s disease (PD) and LID using well-established behavioral assays.

Project Description:
Our methodology, known as bacTRAP, enables selective immunoprecipitation of all translated mRNAs from genetically specified individual cell types within heterogenous cell populations without requiring the separation and isolation of cells from tissue. We have obtained the transcript profile of ChIs in the striatum of a bacTRAP pre-clinical model line that utilizes choline acetyltransferase (ChAT) as a driver. A subset of druggable genes that are enriched in ChIs has been identified by their comparison with the transcript profiles from 140 additional cell types representative of the broader CNS and obtained from their corresponding bacTRAP pre-clinical model lines. We have mined the literature for supporting evidence to confirm the selective expression of potential targets and have then looked for pharmacological and biochemical evidence that would support a functional hypothesis for the target in reducing the hyperactivity of ChIs.  We will utilize a small molecule that fulfills the criteria to determine their effectiveness in reducing behavioral manifestation of LID in classic lesion model of PD in pre-clinical models.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
LID is one of the major complications of current PD therapy, but there is no satisfactory therapy to prevent or reduce LID.

Anticipated Outcome:
We will be able to determine if a candidate small molecule can reduce LID in a pre-clinical model of PD.  If the result is positive, we will plan a pilot study in PD patients with LID using this small molecule.