Study Rationale: The dopamine-producing cells that are lost in Parkinson’s disease (PD) express a unique type of cell-surface protein called the M5 muscarinic acetylcholine receptor. The presence of this unique receptor presents a unique opportunity to correct the changes in activity induced in these neurons by the accumulation of pathological forms of alpha-synuclein.
Hypothesis:Our broad hypothesis is that activation of the M5 receptor could be used as a novel therapeutic strategy for the treating the symptoms, and perhaps modifying the cause of the underlying disease, in people with PD.
Study Design: To test our hypothesis, we will use a multidisciplinary approach to understand how the M5 receptor interacts with the “parkinsonian state.” To do this we, will examine how M5 receptors alter the firing rates of dopamine-producing neurons and affect the changes in motor behavior in preclinical models of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: The successful completion of these studies will provide the preclinical rationale for the development of M5 modulators for the symptomatic and possibly disease-modifying treatment of PD.
Next Steps for Development: The next steps would require medicinal chemistry efforts to develop M5 modulators that can reach the relevant brain regions and have suitable pharmacokinetic properties for clinical use.