Objective/Rationale:
There is an urgent need to understand the cell processes that contribute to the cause of Parkinson’s disease. Parkin is an active enzyme within the cell that provides a benefit to neuronal health in the normal brain. Parkin malfunction is thought to contribute to Parkinson’s disease through the inability to clear damaged mitochondria from neurons. In this project researchers aim to identify factors that reduce Parkin activity and test whether inhibition of such negative regulators can enhance its normal, beneficial actions.
Project Description:
Researchers will first identify negative regulators of Parkin by studying a class of proteins called “de-ubiquitinating enzymes” (DUBs) that counter-act the ubiquitin-ligase activity of Parkin and clearance of damaged mitochondria (“mitophagy”). The scientists have access to a unique resource, a collection of all known human DUBs, and will test all enzymes in this collection for their effect on Parkin-mediated modification of cellular proteins and mitophagy. They will employ genomic screening technologies and biochemical methods to identify DUBs that suppress Parkin activity in healthy cells. They then can test whether inhibition of these DUBs enhance Parkin activity to provide significant therapeutic benefit to the patients.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The identification of DUBs that suppress Parkin activity offers a novel strategy for treatment of Parkinson’s disease. This study will test whether the inhibition of the DUBs will enhance Parkin activity and thus can provide a benefit to patients. Further studies will enable the development of chemical compounds that inhibit the identified DUBs. Current treatments for PD only address the symptoms, so inhibition of a DUB enzyme could provide the first disease-modifying therapy to treat Parkinson’s.
Anticipated Outcome:
Researchers anticipate to identify novel drug targets that suppress Parkin activity in neurons. These results will provide a new avenue for the development of treatments for Parkinson’s disease by enhancing the cellular defense against mitochondrial damage, which can lead to neuronal death.
Final Outcome
Parkin is a gene that is frequently mutated in people with Parkinson's disease. Reduced parkin activity in cells contributes to severe neuronal deficits and nerve cell death. In order to enhance parkin activity, we have explored whether cells employ additional mechanisms to reduce parkin activity that may contribute to reduced neuronal fitness. We have explored a new class of proteins, "De-ubiquitinating enzymes" (DUBs), as potential candidates that inhibit parkin activity. We tested all 92 DUBs present in the human genome and successfully identified eight candidate proteins as suppressors of parkin activity. Our results demonstrate that parkin activity is suppressed in cells and offers the opportunity to develop small molecule compounds that counteract this reduction in activity. In the future, we plan to develop inhibitors against these proteins in order to restore parkin activity to normal levels in cells from Parkinson's disease patients.
March 2015