While neurodegeneration in Parkinson’s disease (PD) affects many cells, dopamine neurons are particularly vulnerable, and their loss drives many of the major motor difficulties in PD. To date, the inner workings of the dopamine neurons themselves have been extensively studied to identify sources for this selective vulnerability. However, neurons in the brain are heavily interconnected and interdependent with their surrounding cells and circuitry. Understanding how the “neighborhood” in which dopamine neurons live and function influences their well-being is a critical missing piece in the puzzle of Parkinson’s disease.
We hypothesize that circuit properties of incoming neuronal connections (synapses), surrounding non-neuronal cells (glial cells), and key modulatory cells (those that produce the chemical signal acetylcholine) contribute to dopamine neuron loss in PD.
We will evaluate circuit contributions to dopamine neuron dysfunction in PD using state-of-the-art mouse genetic models and patient-derived stem cell models (organoids). Our team members bring unique, specialized expertise that allows us to isolate and manipulate each of these three components (synapses, glia and neuromodulators) individually to test its role in dopamine neuron degeneration. In addition to functional manipulations, we will capture the molecular signatures of the connections dopamine neurons make with each of its “neighbors” to determine which are most disrupted in PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Recognizing new processes that cause dopamine neuron demise in PD creates new opportunities for intervention. Our bidirectional tests of function may identify not only circuit properties that accelerate disease, but also identify factors that promote resistance to cell death.
Next Steps for Development:
Our study couples functional perturbations with precise molecular discovery efforts with the hope of being able to use the specific molecular signatures as targets. We expect that a deeper understanding of the overall pros/cons to manipulating the identified circuit property(ies) will be necessary, including species and molecular target-related issues.