Mutations in the Parkin gene are the most common cause of recessive familial Parkinson’s disease. Additionally, the Parkin protein may also be inactivated in idiopathic (cause unknown) disease. Parkin can direct the degradation of damaged mitochondria. This project aims to identify small molecules that have the potential to activate and/or stabilize Parkin’s structure.
Recent structural data for Parkin show a “closed” structure that is consistent with its low enzymatic activity. Researchers have applied molecular modeling techniques to provide an all-atom resolution of full-length Parkin. They now will identify compounds that promote Parkin activation, which then will be validated by cellular high-content imaging of mitochondrial degradation as a read-out for Parkin activation/activity. Recovered hits will feedback into further rounds of virtual and functional characterization to build a repository of Parkin-activating compounds.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Several therapeutic opportunities may exist along Parkin’s multistep activation process, and strategies aiming at safely activating and maintaining Parkin in an active state could prove beneficial and might open up new avenues to treat Parkinson’s disease in the future.
The researchers expect to identify small molecule Parkin activators. In subsequent follow-up studies and using structure-function-based drug design, these could be further developed into neuroprotective agents.