forget” to take damaged mitochondria to the recycling center, resulting in build-up of toxic waste and, eventually, early onset of the disease.
“If the recycling mechanism isn’t functioning properly, those neurons die,” Hannink said.
Peptides behave like drug molecules
Hannink recently published research on the PGAM5 pathway in the Journal of Biological Chemistry along with MU graduate students Jordan M. Wilkins and Cyrus McConnell and fellow Biochemistry faculty member, Peter Tipton.
While its basic nature hides it from the view from the general public, this research takes a large step in the science of Parkinson’s disease.
Beyond defining the regulation of a pathway largely unstudied, their work discovered that a peptide regulates the pathway. Importantly, this peptide is able to alter the activity of the PGAM5 protein and stimulate an alternative recycling pathway for mitochondria.
Peptides are a clear signpost on a path toward drug development.
“Any time you can identify a biological process that is regulated by a peptide, that peptide becomes a lead candidate in the search for small, drug-like molecules that will act the same way,” Hannink said.
For Parkinson’s Disease, the goal is to find ways to repair the mitochondria recycling process.
“We propose that, by regulating PGAM5, it may be possible to restore mitochondrial quality control to dopaminergic neurons of patients with Parkinson’s and lessen the severity of the disease,” Hannink said.
While Hannink’s findings are exciting, there are also nuances to consider.
His research focuses on familial Parkinson’s disease, and it remains unknown whether sporadic Parkinson’s is also due to a defective mitochondrial recycling pathway. Sporadic Parkinson’s accounts for the vast majority of cases and typically affects older people.
It’s not clear if the PGAM5 pathway is also defective in those cases, Hannink said.
The next step of his research is to identify a small molecule that can regulate the PGAM5 protein in cells, just as the peptide did in his test-tube experiments.
Hannink thinks that development of a drug based on the PGAM5 pathway could be useful in restoring mitochondrial recycling in certain cells – like neurons affected in Parkinson’s – while blocking this recycling pathway in other cells, — like cancer cells.
The idea also needs to be tested using mice as a model system. The goal of those experiments will be to determine if the PGAM5 protein can stimulate alternative recycling pathways that can clean up and recycle damaged mitochondria pathway in neurons of mice.