This grant builds upon the research from a prior grant: Structural Insights into Activated Intermediates of Parkin
Study Rationale:
Parkin is an enzyme that modifies proteins on mitochondria in response to damage. In previous MJFF-funded research, we examined how Parkin changes its conformation as it goes from an inactive form to the active form. We were able to answer part of this question using a three-dimensional image of insect Parkin. We now want to extend our study with additional images and studies of human Parkin.
Hypothesis:
We hypothesize that Parkin inside cells behaves as it does in our model as it moves from an inactive to an active form.
Study Design:
We have obtained a snapshot of Parkin in its active form. But this picture is incomplete and doesn't show us the individual steps by which Parkin becomes active. Parkin identifies damaged mitochondria through two distinct steps: movement of Parkin to the damaged mitochondria and activation of enzyme activity. We want to obtain snapshots of these individual steps. In addition, we want to understand how Parkin selects proteins for modification through studies with protein substrates. In a second set of aims, we propose to validate that what we see in the three-dimensional images corresponds to what happens inside cells. We will use biophysical techniques to measure changes in Parkin at a molecular level and experiments with living cells to test our hypotheses about the process of Parkin activation.
Impact on Diagnosis/Treatment of Parkinson's disease:
Loss of Parkin causes a genetic, early-onset form of Parkinson's disease. Together with another Parkinson's disease gene, Parkin is responsible for the identification and recycling of damaged mitochondria. Loss of Parkin leads to accumulation of dysfunctional mitochondria, which causes the disease in these patients. We believe that making Parkin more active will slow or stop the progression of Parkinson's disease in non-genetic forms of the disease. To develop therapies targeting Parkin, we first need to visualize Parkin in its different states and understand the process of its activation.
Next Steps for Development:
Images of human Parkin will be important for identifying drug targets that could potentially increase Parkin activation.