Study Rationale: Dopamine neurons are particularly vulnerable to death in Parkinson’s disease (PD), and their loss is one of the main causes of movement problems in people with PD. Dopamine neurons have been widely studied to understand their vulnerability in PD, however, the influence of their surrounding environment remains under-studied and is a great area of interest for our team to understand its role in the function and well-being of dopamine neurons in PD.
Hypothesis: We hypothesize that components of the circuitry in which dopamine neurons are embedded –including astrocytes, neuromodulatory cells and the machinery of the synapses that link neurons together — contribute to their vulnerability in PD.
Study Design: We have developed state-of-the-art tools to specifically isolate synapses, astrocytes and modulators that control protein homeostasis. Using unique and highly selective approaches, we will manipulate these circuit components and determine their effect on dopamine neuron dysfunction in PD. We will use mice and human cell-derived organoids as PD model systems and determine which manipulations slow or accelerate dopamine neuron death and dysfunction.
Impact on Diagnosis/Treatment of Parkinson’s disease: Identification of novel processes will facilitate the development of more targeted interventions and contribute to the understanding of the underlying causes of vulnerability of dopamine neurons in PD.
Next Steps for Development: Future work will be necessary to understand the detailed molecular mechanisms by which circuit components contribute to the vulnerability of dopamine neurons. We have already generated a preliminary list of molecular candidates. These candidates represent potential clinical targets for improved PD therapies.