Study Rationale:
Previous work has shown how the loss of dopamine neurons affects brain activity. In this program, we will determine how brain activity influences the neurodegeneration that causes Parkinson’s disease (PD). To understand the onset of disease, we will identify the earliest changes in brain activity and use them to infer the mechanisms involved. We will also manipulate activity directly and determine how it interacts with known genes to produce degeneration.
Hypothesis:
We hypothesize that abnormalities in neural activity do not simply reflect but, actually, cause PD. Our lack of knowledge about the role of neural activity in Parkinson’s makes it difficult to understand how other, identified factors contribute to disease.
Study Design:
We will use two models of PD, one based on over-expression of the pathogenic protein alpha-synuclein and the other based on a direct increase in activity. The strategy is to (i) identify the earliest events along the pathway to degeneration and to (ii) correlate these with the selective vulnerability of particular neurons to PD. These approaches will reveal the processes specifically affected by PD. We will also determine how neural activity intersects with factors previously implicated in PD, providing a foundation to understand how they cause degeneration.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
With greater understanding around the onset of disease, we can further investigate how genetic and environmental factors conspire to produce PD. This will open entirely new areas to arrest and prevent the underlying degeneration.
Next Steps for Development:
First, we will begin work to understand how genes implicated in PD contribute to degeneration, leading to more appropriate targets for therapeutic intervention. Second, further research can seek to suggest interventions that modulate neural activity.