Study Rationale: Most previous work on brain circuitry in Parkinson’s disease (PD) has focused on what happens after the loss of dopamine neurons. However, we know that changes in the function of neural circuits precede cell death. By understanding these changes, we wish to obtain insight into the earliest events in degeneration, which are presumably also the most amenable to therapeutic intervention.
Hypothesis: We hypothesize that PD starts with changes in normal brain function that eventually progress to neurodegeneration.
Study Design: We have found that two genes central to PD (alpha-synuclein and glucocerebrosidase) both impair the release of neurotransmitters and hence information exchange at synapses, the sites where neurons connect. In this study, we will characterize the progression from this functional deficit to neurodegeneration, identifying compensatory as well as pathogenic mechanisms. Conversely, we have found that increased neural activity alone can also injure dopamine neurons in the same pattern observed for PD. Hence, we will also explore the basis for this selective vulnerability.
Impact on Diagnosis/Treatment of Parkinson’s disease: By studying the earliest events leading to PD in genetically defined model systems and elucidating the mechanisms involved, we will identify ways to prevent or arrest the degenerative process.
Next Steps for Development: The physiological changes that result in neurodegeneration are inherently reversible. However, understanding the mechanisms involved will also provide insight into the degenerative process crucial to develop effective therapy as well as into the manifestations of disease.