PD Functional Genomics | 2020
Mechanisms of Mitochondrial Damage Control by PINK1 and Parkin
Study Rationale: Mitochondria are tiny power-generating stations within all cells, including neurons. They are vital energy producers, but when things go wrong, they can spew toxic materials and sicken or kill neurons. The clean-up crew for mitochondria gone wrong is called “mitophagy” (as in “eating mitochondria”) and is directed by two proteins called PINK1 and parkin. Studies of Parkinson’s disease have taught researchers that PINK1, parkin and mitophagy are very important in preventing disease.
Hypothesis: The purpose of this project is to figure out how PINK1, parkin and mitophagy work together to prevent disease. Once Team Hurley knows how they work together, they hope to figure out how to make them work faster and better, so that they can prevent Parkinson’s disease from ever starting.
Study Design: Team Hurley thinks of PINK1, parkin and the proteins of mitophagy as nanomachines. They call their type of research “mechanistic” because it seeks to understand how these machines work. Team Hurley relies heavily on the most powerful light and electron microscopes available, and they also use genome engineering of stem cells to make versions of neurons that are easier to study.
Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Hurley’s dream is to understand PINK1, parkin, and mitophagy so well that they can build a computerized description of the pathway that will be able to predict which drugs and treatments will help the mitochondrial clean-up crew enough to prevent or cure disease.
If successful, the project will provide a therapeutically actionable basis for where and how mitophagy can best be activated to promote the health and longevity of the dopaminergic neurons affected in Parkinson's Disease. View Team Outcomes.
Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.
Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.
A RAB7A phosphoswitch coordinates Rubicon homology protein regulation of PINK1/Parkin-dependent mitophagy
Team Hurley has unraveled a novel mechanism of mitophagy regulation, involving proteins that have been associated with Parkinson’s disease (PINK1, Parkin, Rabs). Overall, the work shows that PINK1/Parkin-mediated mitophagy is mechanistically controlled through the molecular switch of TBK1-dependent phosphorylation of Rab7A thus favoring the activation of Pacer, a positive regulator of autophagy. The team combines structural and mechanistic work to hypothesize how mutations in these genes may be involved in Parkinson’s disease.