The proposed research will contribute to our fundamental understanding of the causes of neuronal loss in Parkinson's disease (PD), a key step to accelerate the development of effective treatments. PD is the second most common neurodegenerative disease and despite decades of research, our most effective treatments only alleviate symptoms, rather than alter disease progression. A likely reason for this is our incomplete understanding of the disease mechanism. Thus, to develop effective treatments, and even prevent PD, we need to understand why neurodegeneration is occurring in the first place. Two important concepts have been integral in furthering our understanding of PD: Firstly, neurons that die in PD tend to be highly developed and active cells. And secondly, through the genetic study of PD, it appears that neurodegeneration is occurring due to disruption to the systems that supply energy within neurons. Thus, a promising avenue of research is to explore how energy use varies in different neurons, especially when considering the size and activity of these cells.
Recently, we found that larger and more complex neurons utilize more energy, and as a consequence, have increased cellular stress. This, in turn, makes them more vulnerable to degeneration. These initial findings were made in a part of the brain well known to degenerate in PD. The research in this proposal will look to see whether this idea - that neuron size and complexity, and the associated elevated energetic requirements - can explain why other areas of the brain degenerate during PD. Furthermore, we will determine the molecular mechanisms that drive these neurons to grow in such a way that render them vulnerable in PD. These insights will then put us in a position to develop animal models that better replicate the disease seen in humans: a crucial step in PD research.