Study Rationale: The motor symptoms of Parkinson's disease (PD) result from the degeneration of dopamine-producing neurons in a brain area called the substantia nigra pars compacta (SNc). Recent findings suggest that the SNc is diverse, and is comprised of dopamine neurons with distinct properties. How these dopamine neuron “subtypes” contribute to movement, and how they are affected in PD, remains unknown.
Hypothesis: We hypothesize that the SNc is comprised of dopamine neuron subtypes that promote and inhibit movement and that selective loss of pro-motor neurons in PD causes an imbalance in dopamine neuron subtypes that underlies the motor symptoms of PD.
Study Design: We will separate dopamine neurons in the SNc into their distinct genetic subtypes, which will allow us to study their specific physiological, anatomical and functional properties. We will also determine the molecular and circuit mechanisms underlying the dysfunction of dopamine neurons in the LRRK2 preclinical model of PD.
Impact on Diagnosis/Treatment of Parkinson's disease: Characterizing which dopamine neuron subtypes degenerate and which circuits are dysregulated in PD could enhance enhance efficacy of deep-brain stimulation in people with PD. In addition, identifying the molecular targets of the hyperactive LRRK2 enzyme will be critical for optimizing drugs that inhibit LRRK2 for clinical application in treating PD.
Next Steps for Development: Defining pro- and anti-motor dopamine circuitry could be used to inform the development of electrical, pharmacological and chemical genetic approaches for the rescue of circuit function in people with PD.