Identification of Parkin Activators through Structure-Function Analyses
Parkin Therapeutic Development, 2013
Objective/Rationale: † † † † † ††
Mutations in the Parkin gene are the most common cause of recessive familial Parkinsonís 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 Parkinís structure.
Recent structural data for Parkin show a ďclosedĒ 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 Parkinsonís Disease: † † † † † † † † † ††
Several therapeutic opportunities may exist along Parkinís 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 Parkinsonís disease in the future.
Anticipated Outcome: † † † † †
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.
Associate Professor of Neuroscience at Mayo Clinic
Location: Jacksonville, Florida, United States