This grant builds upon the research from a prior grant: Structural Insights into Activated Intermediates of Parkin
Study Rationale:
Loss of proteins responsible for removing damaged mitochondria (the cell power plants) is the most common cause of young-onset Parkinson’s disease (YOPD). Parkin and PINK1 are key proteins in this mitochondrial quality control system and often mutated in YOPD. After defective mitochondria are detected by PINK1, Parkin tags the mitochondria for recycling by attaching a signal, ubiquitin, to the mitochondrial surface. Understanding how this signaling works at the molecular level will help the development of diagnostics and therapies to improve mitochondrial health in patients.
Hypothesis:
We want to understand how the ubiquitin signal is attached to the mitochondria and why some seemingly benign mutations in parkin cause YOPD.
Study Design:
We will use the techniques of structural biology (e.g., X-ray crystallography) to take pictures of parkin in different conformations. Previous 3D structures have shown us how parkin is turned on by PINK1. We now want to obtain images of the process of ubiquitin attachment.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our first structure explained why some mutations in parkin cause disease, but other mutations remain unexplained. Images of mutant proteins and the steps of ubiquitin attachment will clarify what types of therapies are possible and how to develop them.
Next Steps for Development:
The next step, already ongoing in other laboratories, is to use our knowledge of how parkin is turned on to search for drugs to increase the recycling of mitochondria.