Objective/Rationale:
Parkinson’s disease (PD) is frequently associated with mutations in the gene that encodes Parkin, a protein that detects and degrades dysfunctional mitochondria. While removing damaged mitochondria is important for neuron survival, it is equally essential to detect and remove any toxic proteins that leak out of damaged mitochondrial and kill neurons. This study focuses on a novel mechanism to remove toxic mitochondrial proteins, therefore allowing for the long-term survival of neurons.
Project Description:
Previous research shows that a key toxic protein released by damaged mitochondria is targeted for degradation by Parc, a protein that is very similar to Parkin. As a consequence, neurons that lack Parc are more vulnerable to mitochondrial damage. This project will focus on Parc and determine whether it can degrade other toxic mitochondrial proteins, as well as damaged mitochondria. Importantly, researchers will examine whether Parc and Parkin function together to ensure optimal neuronal survival. They will test these ideas using neuronal cultures as well as pre-clinical models that are deficient for both Parc and Parkin.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The discovery that Parc functions in a pathway typically used by Parkin provides strong rationale for investigating whether mutations in Parc, like Parkin, are associated with PD. In particular, PD patients who develop the disease early in life may have mutations in both Parc and Parkin. Importantly, results could indicate that a therapeutic strategy that provides the combined delivery of Parc and Parkin together may be more effective in keeping neurons alive than Parkin alone.
Anticipated Outcome:
This project will reveal where, when and how Parc acts to allow neurons to survive mitochondrial damage. Researchers also anticipate that deficiency of both Parc and Parkin could generate a pre-clinical model that exhibits the full spectrum of PD. Most importantly, these results could bring focus to a previously unappreciated aspect of Parkin biology: that Parc, a Parkin-related protein, functions in the same pathway as Parkin to ensure optimal neuronal survival during mitochondrial injury.
Final Outcome
Our results show that optimal survival of neurons in situations of injury (mitochondrial damage) requires the cooperation of two proteins: Parkin and Parc. Parkin, a protein that is mutated in people with Parkinson's disease, is important for eliminating any damaged mitochondria from neurons -- a phenomenon that is being extensively studied in many labs. We have found that Parc, a protein similar to Parkin, is also important in situations of mitochondrial damage but with a distinct function. Unlike Parkin, Parc is not targeted to the damaged mitochondria, but instead surrounds these damaged mitochondria and targets for removal the cytochrome c protein, which is released from damaged mitochondria and has the potential to kill neurons. Thus, Parkin and Parc have complementary but distinct functions, and the loss of both Parkin and Parc together has an outcome that is worse that loss of either protein alone.
April 2015