Study Rationale:
Parkinson’s disease (PD) begins decades before it compromises the ability to move about in the world and sleep through the night. Understanding how the dysfunction of brain circuits begins and then evolves to cause difficulty in moving and sleeping will allow us to diagnose PD earlier — increasing our chances of halting disease progression — and to better treat the disease once it appears.
Hypothesis:
The progressive damage to dopamine-releasing neurons results in staged disruption of neural circuits in larger and larger parts of the brain, ultimately leading to both motor and sleep deficits characteristic of PD.
Study Design:
Our plan is to study a new genetically engineered mouse model that manifests a progressive, levodopa-responsive parkinsonism. Importantly, this mouse faithfully reproduces the human staging of pathology in key brain circuits. Using the most advanced methods available for studying and manipulating genetically defined brain circuits, the causal linkage between circuit dysfunction and motor and sleep behavior will be determined.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
A better understanding of how the circuit dysfunction underlying PD is staged should allow earlier diagnosis — enhancing the potential benefit of disease-modifying therapies — and better treatment strategies for later-stage patients.
Next Steps for Development:
A firmer grasp of the sequence of events leading to the circuit dysfunction underlying motor and sleep symptoms should allow better targeting of pharmacological and genetic therapies. For example, to assess the causal role of a specific brain circuit in the emergence of levodopa-responsive motor symptoms in our mouse model, we have used an adeno-associated virus-based gene therapy to boost the conversion of levodopa to dopamine. These experiments suggest that this circuit-specific gene therapy effectively increases the ability of systemic levodopa to alleviate motor deficits. These experiments demonstrate how a better understanding of circuit dysfunction in PD could lead to novel treatment strategies.